Clinical trial NCT00998010
Conditions: Brain and Central Nervous System Tumors
Keywords: adult giant cell glioblastoma adult glioblastoma adult gliosarcoma
Sponsor: Jonsson Comprehensive Cancer Center
Start date: 2011-10-03; Completion date: 2018-04-20
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving bortezomib together with temozolomide and radiation therapy may kill more tumor cells and allow doctors to save the part of the body where the cancer started.

PURPOSE: This phase II trial is studying the side effects and how well bortezomib works when given together with temozolomide and regional radiation therapy in treating patients with newly diagnosed glioblastoma multiforme or gliosarcoma.

Detailed description:
OBJECTIVES:

Primary

* Estimate the overall survival at 2 years of patients with newly diagnosed glioblastoma multiforme treated with bortezomib in combination with temozolomide and regional radiotherapy followed by maintenance therapy comprising bortezomib and temozolomide.

Secondary

* Investigate further the safety and tolerability of this regimen in these patients.
* Determine the molecular characterization of tumor tissue and correlate these findings with response.

OUTLINE: This is a multicenter study.

* Adjuvant chemotherapy: Patients receive bortezomib IV on days 1, 4, 8, 11, 29, 32, 36, and 39 and oral temozolomide on days 1-42. Patients undergo external-beam fractionated regional radiotherapy 5 days a week for 6 weeks in the absence of disease progression or unacceptable toxicity.
* Maintenance: Beginning 2-6 weeks after radiotherapy, patients receive bortezomib IV on days 1, 4, 8, and 11 and oral temozolomide on days 1-5. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Tumor tissue samples are collected at baseline (from surgery) and periodically during study for further analysis.

After completion of study therapy, patients are followed up periodically.

Arms: arm 1: Patients receive bortezomib IV on days 1, 4, 8, 11, 29, 32, 36, and 39 and oral temozolomide on days 1-42.Patients undergo external-beam fractionated regional radiotherapy 5 days a week for 6 weeks in the absence of disease progression or unacceptable toxicity.2-6 weeks after radiotherapy, patients receive bortezomib IV on days 1, 4, 8, and 11 and oral temozolomide on days 1-5.Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: bortezomib + temozolomide+ radiation therapy
Intervention descriptions: intervention 1: Patients will be treated with Bortezomib at 1.3 mg/m2 IV on days1,4,8,11,29,32,36 and 39 and Temozolomide on 75mg/m2 daily during radiation. External beam fractionated regional radiation will be given on consecutive week days at 200 centigray (cGy) daily doses to a total dose of 6000 cGy.

Protocol documents:
Prot_SAP_000.pdf: 
 
 Phase II Trial of VELCADE® (Bortezomib) in Combination with Temozolomide and 
Regional Radiation Therapy for Upfront Treatment of Patients with Newly-diagnosed 
Glioblastoma Multiforme. 
 
 
Protocol Version: Date of Protocol: 
Original January 22, 2009 
Amendment 1 February 14, 2011 
Amendment 2 May 31, 2012 
Amendment 3 August 1, 2012 
Amendment 4 January 09, 2013 
Amendment 5 March 13, 2013 
Amendment 6 November 19, 2013 
Amendment 7 February 11, 2014 
 
Principal Investigator 
Dr. Albert Lai 
University of California at Los Angeles 


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STUDY PROTOCOL 
 
Protocol Number X05303 
 
 
Phase II Trial of VELCADE® (Bortezomib) in Combination with 
Temozolomide and Regional Radiation Therapy for Upfront Treatment of 
Patients with Newly-diagnosed Glioblastoma Multiforme.   
 
Protocol Version: 
 
Date of Protocol: 
Original 
 
 
January 22, 2009 
 
 
 
Amendment 1  
 
February 14, 2011 
 
 
 
Amendment 2  
 
May 31, 2012 
 
 
 
Amendment 3  
 
August 1, 2012 
 
 
 
Amendment 4  
 
January 09, 2013 
 
 
 
Amendment 5  
 
March 13, 2013 
                                       Amendment 6                              November 19, 2013 
                                       Amendment 7                              February 11, 2014 
 
Investigator &Study Center: 
 
Principal Investigator 
 
 
 
 
 
 
 
Co-Principal Investigator 
 
 
Sub-Investigators 
 
 
 
Sub-Site:  
 
 
 
 
 
 
 
*VELCADE is the exclusive trademark of Millennium Pharmaceuticals, Inc., registered in the United 
States and internationally. 


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PROTOCOL SUMMARY 
Title:   
Phase II Trial of VELCADE* (Bortezomib) in Combination with Temozolomide and 
Regional Radiation Therapy for Upfront Treatment of Patients with Newly-diagnosed 
Glioblastoma Multiforme. 
 
Objectives:  
This phase II study will examine the safety and efficacy of bortezomib in combination with 
temozolomide/radiation followed by bortezomib and temozolomide for 2 years (24 28-day 
cycles) in newly-diagnosed patients with glioblastoma.   
 
The primary objective of the study is to: 
 
Estimate the overall survival in subjects with newly-diagnosed glioblastoma 
(GBM) treated with bortezomib/temozolomide/radiation followed by 
bortezomib/temozolomide for 24 cycles until progression is detected or for up to 
24 cycles (~2 years).   
 
The secondary objectives of this study are to: 
 Investigate 
further 
the 
safety 
and 
tolerability 
of 
bortezomib/temozolomide/radiation followed by bortezomib/temozolomide. 
 Collect frozen and paraffin patient tumor tissue to be utilized for MGMT 
promoter methylation and IDH1 genotyping and for correlative molecular 
characterization to be submitted as a separate research study. Tissue must be 
obtained in all study patients from original surgery, and in those patients who 
will be undergoing resection at time of treatment failure and during the follow-up 
period. 
 
Patient population: 
 
This study will be open to newly-diagnosed patients with GBM that have not received other 
therapy other than surgery.  Additionally, a key enrollment inclusion criterion is the 
collection of frozen tissue along with paraffinized tissue.  This is necessary for MGMT 
promoter 
methylation 
and 
IDH1 
genotyping 
studies 
and 
correlative 
molecular 
characterization.  Specific inclusion and exclusion criteria are detailed in section 3.2. 
 
Number of patients: 
 
Total: 50 (over three year enrollment period) 


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Study design and methodology: 
 
This will be a multi-center, open-label, phase II study assessing safety and efficacy in which 
adult newly-diagnosed GBM patients that have had no prior therapy, other than surgery, will 
receive bortezomib, temozolomide, and radiation all starting on day 1 (+/- 2 days) of study.  
Day 1 of the study must be no sooner than 2 weeks from surgery and no longer than 6 weeks 
after surgery, followed by bortezomib and temozolomide after completion of fractionated 
radiation for up to 24 additional cycles if no tumor growth is seen.  At this point, both 
bortezomib and temozolomide will be discontinued, and the patient will be monitored with 
routine MRI surveillance until progression.  There has recently been publication of a phase I 
study that found no significant toxicities when bortezomib at a dose of 1.3 mg/ m2 (days 1, 4, 
8, 11, 22, 25, 29, and 32) was combined with brain radiation and temozolomide for patients 
with newly-diagnosed or recurrent gliomas (Kubicek, Werner-Wasik et al. 2008).  Of note, in 
the recurrent cases, patients had received prior radiation.  Based on those findings, we will 
utilize the same bortezomib dosing used in that protocol, although the schedule will be 
slightly altered. 
 
Patients will receive 1.3 mg/m2 bortezomib subcutaneous on days 1, 4, 8, 11, 29, 32, 36, and 
39 and temozolomide 75 mg/m2 daily during radiation. Bortezomib will be administered 
beginning on the first day of radiation with temozolomide.  External beam fractionated 
regional radiation will be given on consecutive week days at 200 cGy daily doses to a total 
dose of 6000 cGy.  After a 2-6 week rest (for temozolomide and bortezomib) following 
completion of radiation therapy, a maintenance phase (post-RT) of temozolomide will be 
restarted at 150 mg/ m2/day for 5 days out of every 28.  (If this is tolerated, subsequent cycles 
will be given at 200 mg/ m2/day).  Also, bortezomib at 1.3 mg/m² will be given on days 1, 4, 
8, and 11 of a 28 day cycle commencing on the first day of temozolomide.  Temozolomide 
will not be increased greater than 200 mg/m2/day.  No increases in bortezomib above 1.3 
mg/m² will be made.  Treatment with bortezomib and temozolomide will continue for 24 
additional 28 day cycles from radiation therapy if there is no evidence of progression.  At that 
time, both bortezomib and temozolomide will be stopped if there is no evidence of disease 
progression.  Note: If unacceptable toxicities after the first 12 cycles are observed, per 
investigator’s discretion, the bortezomib dosing schedule may be changed to 1.3 mg/m2 
weekly for 3 weeks on and 1 week off, with the possibility of further reduction if necessary to 
1.3 mg/m2 biweekly. 
 
Treatments administered: 
 
1) Radiotherapy 
2) Temozolomide 
3) Bortezomib 
 
Efficacy data collected: 
 
The following evaluations will be conducted to assess the efficacy of the combination of 
bortezomib, temozolomide and radiation: 
 
 Overall survival 
 Time to progression 
 Progression free survival 
 Radiographic response (when evaluable) 




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month survival rate is 55% (median survival 21 months) for the new treatment and 40% 
(median survival 14 months) for the standard treatment (based on (Stupp, Mason et al. 2005), 
3.  The 18-month survival rate is estimated using the Kaplan-Meier method, 4.  Test statistics 
– Z-test, Type I error=0.05, 5. N=50 (total patients).  In a performed simulation, the power is 
70% for 1-sided test.  
 
After 10 patients with newly-diagnosed GBM are treated, an interim analysis will be 
conducted.  If 3 or more patients have experienced unacceptable toxicity (defined as a grade 4 
non-hematologic toxicity or any grade 5 toxicity), enrollment will be suspended pending full 
assessment of safety risks to determine if the study should continue.  Otherwise, patient 
accrual will continue.   
 
The primary endpoint will be total survival from the date of surgical-pathological diagnosis.  
For the final analysis, endpoint results will be compared with the results on comparable 
patients whose data are available through the UCLA Neuro-Oncology Department database.  
These comparable patients were all newly diagnosed GBM patients who were treated on 
research protocols and similar to the patients in the present study insofar as were seen at a 
tertiary center and enrolled into clinical trials early after diagnosis.  The primary analysis will 
utilize a Cox proportional hazards model including age, KPS, and extent of resection.  This 
allows for adjustment for major prognostic factors. 
 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION AND STUDY RATIONALE ........................................................... 11 
1.1 
Overview of the Disease ...................................................................................... 11 
1.2 
VELCADE (bortezomib) for Injection ................................................................ 12 
1.2.1 Scientific Background ............................................................................ 12 
1.2.2 Nonclinical Pharmacology ....................................................................... 13 
1.2.3 Nonclinical Toxicity ................................................................................ 14 
1.2.4 Clinical Pharmacokinetics and Pharmacodynamics ................................ 14 
1.2.5 Clinical Experience .................................................................................. 16 
1.2.6 Potential Risks of Bortezomib ................................................................. 20 
1.2.7 Precautions and Restrictions .................................................................... 26 
1.3 
Temozolomide (see product insert) ..................................................................... 27 
1.3.1 Scientific Background .............................................................................. 27 
1.3.2 Nonclinical Pharmacology ....................................................................... 27 
1.3.3 Nonclinical Toxicity ................................................................................ 27 
1.3.4 Clinical Pharmacokinetics and Pharmacodynamics ................................ 27 
1.3.5 Clinical Experience .................................................................................. 27 
1.3.6 Potential Risks of Temozolomide ............................................................ 27 
1.4 
Study rationale and selection of drug doses ......................................................... 27 
2 
STUDY OBJECTIVES .................................................................................................... 30 
2.1  Primary Objective ..................................................................................................... 30 
2.2 
Secondary Objectives........................................................................................... 30 
3 
INVESTIGATIONAL PLAN .......................................................................................... 31 
3.1 
Overall Design and Plan of the Study .................................................................. 31 
. ............................................ 33 
3.2 
Selection of Patients ............................................................................................. 36 
3.2.1 Inclusion Criteria ..................................................................................... 36 
3.2.2 Exclusion Criteria .................................................................................... 38 
3.3 
Study Treatments ................................................................................................. 39 
3.3.1 Clinical Trial Materials ............................................................................ 39 
3.3.2 Preparation, Handling, and Storage of Drugs .......................................... 40 
3.3.3 Dose Modification and Delay .................................................................. 43 
3.3.4  Treatment Assignment ............................................................................. 48 
3.3.5  Blinding, Packaging, and Labeling ............................................................ 48 
3.3.6 Concomitant Treatment ........................................................................... 48 
3.3.7 Treatment Compliance ............................................................................. 49 
3.4 
Duration of Treatment and Patient Participation ................................................. 49 
3.5 
Termination of Treatment and/or Study Participation ......................................... 49 
3.6 
Efficacy, Pharmacodynamic/Pharmacogenomic/Correlative studies, and 
Safety Measurements ........................................................................................... 50 
3.6.1 Efficacy Measurements ............................................................................ 50 
3.6.2  Pharmacokinetic/Pharmacodynamic/Pharmacogenomic/Correlative 
Studies .................................................................................................... 51 
3.6.3 Safety Measurements ............................................................................... 52 
4.1 
Definitions............................................................................................................ 52 
4.1.1 Adverse Event Definition ........................................................................ 52 
For this protocol an abnormal laboratory value will not be assessed as an 
AE unless that value leads to discontinuation or delay in 


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treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant 
change from baseline. .............................................................................. 53 
4.1.2  Serious Adverse Event Definition ............................................................. 53 
4.2 
Procedures for AE and SAE Reporting ............................................................... 53 
4.3 
Procedures for Reporting Drug Exposure during Pregnancy and Birth 
Events ................................................................................................................... 55 
5 
STATISTICAL PROCEDURES ..................................................................................... 56 
5.1 
Sample Size Estimation ....................................................................................... 56 
5.2 
Randomization and Stratification ........................................................................ 56 
5.3 
Populations for Analysis ...................................................................................... 56 
5.4 
Procedures for Handling Missing, Unused, and Spurious Data........................... 56 
5.5.1 Baseline Comparisons .............................................................................. 56 
5.5.2 Efficacy Analysis ..................................................................................... 56 
5.5.3 Safety Analysis ........................................................................................ 58 
5.6 
Interim Analysis ................................................................................................... 62 
5.7 
Procedures for Reporting Deviations to Original Statistical Analysis Plan ........ 62 
6 
ADMINISTRATIVE REQUIREMENTS ....................................................................... 63 
6.1 
Product Complaints .............................................................................................. 63 
7 
REFERENCES ................................................................................................................ 64 
VELCADE REFERENCES ......................................................................................................... 66 
8 
APPENDICES ................................................................................................................. 70 
8.1 
Study Flow Chart ................................................................................................. 70 
8.2 
Karnofsky Performance Status Scale (The following table presents the 
Karnofsky performance status scale ) .................................................................. 71 
8.3 
Body Surface Area and Creatinine Clearance Calculations ................................ 72 
8.4 
New York Heart Association Classification of Cardiac Disease ......................... 73 
8.5 
Declaration of Helsinki ........................................................................................ 74 
8.6 
Common Terminology Criteria for Adverse Events Version 3.0 ........................ 78 
8.7 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme ............................... 78 
8.8 
FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 ...................................... 81 
8.9 
Sample Collection and Handling Requirements; 20S Proteasome 
Inhibition Assay ................................................................................................... 81 
8.10 
Sample Collection and Handling Requirements; PK ........................................... 81 
8.11 
Sample Collection and Handling Requirements; PGx ......................................... 81 
8.12 
RADIATION THERAPY GUIDELINES ........................................................... 81 
8.13     Drugs known to be metabolized by CYP450 isoenzyme 3A4 ............................  84 


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List of Tables and Figures in the Text 
Tables 
Table 3-1 
Management of Patients with VELCADE Related Neuropathic Pain 
and/or Peripheral Sensory or Motor Neuropathy ................................................. 39 
 


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Abbreviations List 
Abbreviation 
Definition 
C 
degrees Celsius 
M 
Micromolar 
20S 
20S proteasome subunit 
AE 
adverse event 
ANC 
absolute neutrophil count 
Bc1-2 
B-cell lymphoma-2; a gene that inhibits apoptosis 
BSA 
body surface area 
CAM 
cell adhesion molecules  
Cm 
Centimeter 
CR 
Complete Response 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DNA 
deoxyribonucleic acid 
FDA 
Food and Drug Administration 
GBM 
Glioblastoma 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
Ht 
Height 
IB 
I kappa B kinase; cytokine response kinase that activates 
transcription factor NF-kappa b at serine 32 and 36 
ICAM-1 
intercellular adhesion molecule 1 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
IB 
I kappa B alpha-associated protein kinase 
Kg 
Kilogram 
Ki 
inhibitory constant 
Lbs 
Pounds 
m2 
square meters 
Mg 
Milligram 
Min 
Minute 
mL 
Milliliter 


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Abbreviation 
Definition 
mm3 
cubic millimeters 
Mmol 
Millimole 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NF-B 
nuclear factor-B 
Ng 
Nanogram 
nM 
Nanomole 
p21 
p21(ras) farnesyl-protein transferase 
p27 
cyclin-dependent kinase inhibitor 
p53 
tumor suppressor protein with molecular weight of 53 kDa 
PR 
Partial response 
RT 
Radiation therapy 
SAE 
SQ 
TMZ 
serious adverse event 
subcutaneous 
temozolomide 
UCLA 
University of California at Los Angeles 
US 
United States 
USP 
United States Pharmacopeia 
VCAM-1 
vascular cell adhesion molecule 1 
w/w 
weight-to-weight ratio 
Wt 
Weight 


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1 INTRODUCTION AND STUDY RATIONALE 
1.1 Overview of the Disease 
The incidence of primary malignant brain tumors in the United States (US) is about 17,000 
per year, with approximately 10,000 deaths per year (Wrensch, Minn et al. 2002).  
Glioblastoma is the most frequent, accounting for ~40% of all primary malignant brain 
tumors.  It is the most aggressive form of brain cancer.  Although they are relatively 
uncommon, malignant brain tumors account for significant mortality in the US.  Despite 
optimal treatment with surgery, radiation therapy, and chemotherapy, the prognosis remains 
poor.  Recently, a phase III randomized trial comparing radiation alone with combined 
temozolomide and radiation followed by 6 cycles of temozolomide showed that the addition 
of temozolomide increased median survival from 12.1 months to 14.6 months, increasing 2-
year survival rates from 10.4% to 26.5% (Stupp, Mason et al. 2005).  These results have 
established adjuvant temozolomide and radiation as the standard of care for newly-diagnosed 
glioblastoma.  Nonetheless, there is clearly a need for improvement given that this regimen is 
associated with a two-year survival of only 26%.  The proposed trial will evaluate whether 
the addition of bortezomib to radiation and temozolomide can be safely tolerated, and 
whether this combination has increased efficacy in the treatment of newly-diagnosed 
glioblastoma.  The major safety issues that are anticipated to require close monitoring are 
myelotoxicity (particularly thrombocytopenia), and any unpredicted neurological side effects 
secondary to bortezomib and brain radiation. 
 
Accumulating evidence indicates that NF-kB may be constitutively active in glioblastoma 
(Raychaudhuri, Han et al. 2007).  NF-kB may potentially have a key role in tumor processes 
such as invasion, suppression of apoptosis, angiogenesis, proliferation, and chemotherapeutic 
and radiation resistance.  Thus, targeting NF-kB activation has emerged as an anti-tumor 
strategy.  Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S 
proteasome in mammalian cells.  The 26S proteasome is a large protein complex that 
degrades ubiquitinated proteins.  The ubiquitin-proteasome pathway plays an essential role in 
regulating the intracellular concentration of specific proteins, thereby maintaining 
homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, 
which can affect multiple signaling cascades within the cell.   
 
Bortezomib has gained United States Food and Drug Administration (US FDA) approval for 
myeloma in the relapsed and frontline setting, and in relapsed mantle cell lymphoma.  Its 
primary mechanism of action is thought to be mediated by repression of NF-kB signaling by 
stabilization of IkB (Orlowski and Kuhn 2008).  There is preclinical evidence demonstrating 
activity of bortezomib against glioblastoma (Yin, Zhou et al. 2005; Styczynski, Olszewska-
Slonina et al. 2006).  Bortezomib causes growth arrest of human GBM cell lines and GBM 
explants via NF-kB inhibition that can be enhanced by TNF alpha or TNF-related apoptosis-
inducing ligand (TRAIL) (Yin, Zhou et al. 2005).  The clinical trial experience in actual 
patients has not been published, and is limited to recurrent patients (tamoxifen/bortezomib 
(Cedars-Sinai), temozolomide/bortezomib (City of Hope), and bevacizumab/bortezomib 
(Duke)) Bortezomib and Concurrent External Beam Radiation (Universty of Colorado), 
Bortezomib with Concurrent Fixed Dose Paclitaxel and Radiation (University of Colorado), 
Concomitant Bortezomiband Radiation (NCI), Bortezomib as a Radiosensitizer in Patients 
with Metastatic Melanoma to the Brain who Require Whole Brain Radiation (University of 
Michigan), Bortezomib, Paclitaxel, Carboplatin, and Concurrent Thoracic Radiation Therapy 
(NCCTG).  In other tumor types, there is evidence of enhancement of either temozolomide or 
radiotherapy with concurrent administration of bortezomib (Russo, Tepper et al. 2001; Amiri, 


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Horton et al. 2004; Edelman 2005).  For example, melanoma cells in vitro and in the context 
of murine models were significantly more sensitive when treated with the combination of 
bortezomib and temozolomide compared to temozolomide alone (Amiri, Horton et al. 2004).  
Increased levels of NF-kB activity has been implicated in tumor resistance to temozolomide 
(Bredel, Bredel et al. 2006; Yamini, Yu et al. 2007). 
 
Recently, bortezomib with concurrent radiotherapy and temozolomide has been studied in a 
phase I trial for central nervous system malignancies, including newly-diagnosed and 
recurrent malignant gliomas (Kubicek, Werner-Wasik et al. 2008).  Only temozolomide was 
continued after radiation for maintenance.  At the highest dose used (1.3 mg/m2, days 1, 4, 8 
and 11 of a 21 day cycle given twice), no dose-limiting toxicities were reported.  The most 
frequent toxicities were Grade 1 and 2 stomatitis, erythema, and alopecia.  Grade 3 toxicities 
reported were headache, neuropathy, syncope, hyponatremia, and dyspnea.  This study adds 
to the currently limited experience treating humans with concurrent bortezomib and radiation.   
 
In preclinical models, bortezomib is a radiosensitizer (Davies, Lara et al. 2007).  There are 
ongoing studies utilizing the combination of bortezomib and radiation therapy (RT) for a 
variety of solid tumors.  In a study utilizing bortezomib (0.6 mg/ m² twice weekly) and re-
irradiation for recurrent head-and-neck squamous cell carcinoma (HNSCC), there was no 
clear relationship between the bortezomib/RT combination and observed DLTs (Van Waes, 
Chang et al. 2005).  Particularly, no excessive mucositis was observed.  In case reports in 
which multiple myeloma was treated with concurrent RT and bortezomib, apparent increased 
local GI toxicity was observed (Berges, Decaudin et al. 2008). 
 
In summary,  the rationale for the study is based on:  1) current inadequacy of standard of 
care therapy for newly-diagnosed glioblastoma, 2) preclinical evidence indicating activity of 
bortezomib against glioblastoma and possible synergism with temozolomide and/or radiation,  
and 3) demonstrated feasibility of such a similar study conducted at UCLA and the possibility 
of more rapid enrollment and 4) tissue collection (serum and tumor tissue) and banking for 
correlative studies aimed at understanding biomarkers and mechanisms of tumor response to 
bortezomib within this context. 
 
1.2 VELCADE (bortezomib) for Injection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 




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1.3 Temozolomide (see product insert) 
1.3.1 Scientific Background 
Temozolomide is an oral DNA alkylating agent that is FDA approved for the treatment of 
malignant gliomas.  It is a derivative of dacarbazine and is rapidly converted systemically to 
MTIC.  It interferes with DNA replication via alkylation of specific sites of the nucleotide 
backbone.  Perhaps the most important site is on the O6 position of guanine.  Alkylation of 
this site can be repaired by the enzyme, O-6-methylguanine-DNA methyltransferase 
(MGMT).  Promoter methylation of MGMT has emerged as a marker of response to 
temozolomide. 
 
1.3.2 Nonclinical Pharmacology 
Not applicable 
 
1.3.3 Nonclinical Toxicity 
Not applicable 
 
1.3.4 Clinical Pharmacokinetics and Pharmacodynamics 
See product insert.  http://www.spfiles.com/pitemodar.pdf 
 
1.3.5 Clinical Experience 
See product insert.  http://www.spfiles.com/pitemodar.pdf 
 
1.3.6 Potential Risks of Temozolomide 
See product insert.  http://www.spfiles.com/pitemodar.pdf 
 
1.4 Study rationale and selection of drug doses 
 
The present proposal seeks to investigate whether beneficial effects can be detected when 
bortezomib is combined with first-line treatment with temozolomide/XRT in patients with 
newly-diagnosed glioblastoma.   
 
Accumulating evidence indicates that NF-kB may be constitutively active in glioblastoma 
(Raychaudhuri, Han et al. 2007).  Given the potential for NF-kB to have a key role in tumor 
processes such as invasion, suppression of apoptosis, angiogenesis, proliferation, and 
chemotherapeutic and radiation resistance, targeting NF-kB activation has emerged as an 
anti-tumor strategy.  Bortezomib is a proteasomal inhibitor that has gained FDA approval for 
both myeloma and relapsed mantle cell lymphoma.  Its primary mechanism of action is 
thought to be mediated by repression of NF-kB signaling by stabilization of IkB (Orlowski 
and Kuhn 2008).   There is preclinical evidence of activity of  bortezomib against 
glioblastoma (Yin, Zhou et al. 2005; Styczynski, Olszewska-Slonina et al. 2006).  
Bortezomib causes growth arrest of human GBM cell lines and GBM explants via NF-kB 


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inhibition, and could be enhanced by TNF alpha or TNF-related apoptosis-inducing ligand 
(TRAIL) (Yin, Zhou et al. 2005).  The clinical trial experience in actual patients has not been 
published and is limited to recurrent patients (tamoxifen/bortezomib (Cedars-Sinai), 
temozolomide/bortezomib (City of Hope), bevacizumab/bortezomib (Duke).  In other tumor 
types, there is evidence of enhancement of either temozolomide or radiotherapy with 
concurrent administration of bortezomib (Russo, Tepper et al. 2001; Amiri, Horton et al. 
2004; Edelman 2005).  Increased levels of NF-kB activity has been implicated in tumor 
resistance to temozolomide (Bredel, Bredel et al. 2006; Yamini, Yu et al. 2007). 
 
Recently, bortezomib with concurrent radiotherapy and temozolomide has been studied in a 
phase I trial for central nervous system malignancies, including newly-diagnosed and 
recurrent malignant gliomas (Kubicek, Werner-Wasik et al. 2008).  Only temozolomide was 
continued after radiation for maintenance.  At the highest dose used (1.3 mg/m2, days 1, 4, 8 
and 11 of a 21 day cycle given twice), no dose-limiting toxicities were reported for 
bortezomib.  The most frequent toxicities were Grade 1 and 2 stomatitis, erythema, and 
alopecia.  Grade 3 toxicities reported were headache, neuropathy, syncope, hyponatremia, 
and dyspnea.  This study adds to currently limited experience treating humans with 
concurrent bortezomib and radiation.  In preclinical models, bortezomib is a radiosensitizer 
(Davies, Lara et al. 2007).  There are ongoing studies utilizing the combination of bortezomib 
and RT for a variety of solid tumors.  In a study utilizing bortezomib (0.6 mg/ m² twice 
weekly) and re-irradiation for recurrent head-and-neck squamous cell carcinoma (HNSCC), 
there was no clear relationship between the bortezomib/RT combination and observed DLTs 
(Van Waes, Chang et al. 2005).  Particularly, no excessive mucositis was observed.  In case 
reports in which multiple myeloma was treated with concurrent RT and bortezomib, apparent 
increased local GI toxicity was observed (Berges, Decaudin et al. 2008). 
 
Another feature of this trial is the requirement for frozen and paraffinized patient tumor tissue 
for molecular characterization.  We have recently completed enrollment of a similar trial in 
which frozen tumor tissue was required (Lai, Filka et al. 2008).  This is a 70-patient trial 
examining the safety and efficacy of upfront bevacizumab, temozolomide, and radiaton for 
the treatment of newly-diagnosed glioblastoma.  The detailed tissue interrogation for the 
bevacizumab/TMZ/RT has not yet begun, although fairly detailed plans have been 
formulated.  Planned assays for the bevacizumab/TMZ/RT study include MGMT promoter 
methylation and immunohistochemistry VEGF and VEGFR immunohistochemistry gene 
expression, SNP (for copy number), and methylation microarray based profiling.  We 
anticipate that much of the experience and information gained from characterizing this tissue 
will be directly applicable to the proposed patient sample set.   
 
In summary,  the rationale for the study is based on:  1) current inadequacy of standard of 
care therapy for newly-diagnosed glioblastoma, 2) preclinical evidence indicating activity of 
bortezomib against glioblastoma and possible synergism with temozolomide and radiation,  
and 3) demonstrated feasibility of such a similar study conducted at UCLA and the possibility 
of more rapid enrollment and tissue interrogation leading to understanding of biomarkers and 
mechanisms of tumor response to bortezomib within this context. 
 
The selection of RT and TMZ dosing is based entirely on the Stupp protocol for newly-
diagnosed GBM (Stupp, Mason et al. 2005).  Based on the recent phase I study, patients will 
receive 1.3 mg/ m²/day on days 1, 4, 8, 11, 29, 32, 36, and 39 during radiation (Kubicek, 
Werner-Wasik et al. 2008).  The 1.3 mg/ m²/day dose (days 1, 4, 8, and 11 of a 28 day cycle) 
will be the maintenance dose for all patients.  This is the dose previously used in combination 


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with TMZ maintenance therapy without evidence of significant toxicity (personal 
communication, Dr. Portnow, City of Hope, Duarte, CA).    


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2 STUDY OBJECTIVES 
This phase II study will have a Radiation phase with bortezomib in combination with 
temozolomide/radiation followed by a Maintenance phase of bortezomib and temozolomide 
following completion of radiation for 2 years (24 28-day cycles). 
 
2.1  Primary Objective 
The primary objective of this study is to: 
 Estimate the overall survival  
Investigate the safety and tolerability of this drug combination (bortezomib with 
temozolomide/radiation followed by bortezomib and temozolomide maintenance 
for 2 years if there is no progression, in which case both drugs will be stopped, 
and the patient will obtain routine MRI surveillance until progression) in newly-
diagnosed patients with glioblastoma.  
 
2.2 Secondary Objectives 
The secondary objectives of this study are to: 
 
 Investigate 
further 
the 
safety 
and 
tolerability 
of 
bortezomib/temozolomide/radiation followed by bortezomib/temozolomide. 
 Collect frozen and paraffinized patient tumor tissue for MGMT promoter 
methylation analysis and IDH1 genotyping and for correlative studies. Tissue 
must be obtained in all study patients from the original surgery, and in those 
patients who will be undergoing resection at time of treatment failure and during 
the follow-up period. 
 


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3 INVESTIGATIONAL PLAN 
 
3.1 Overall Design and Plan of the Study 
 
This study will be a multi-center, open-label, phase II study assessing safety and efficacy in 
which adult newly-diagnosed GBM patients that have had no prior therapy other than surgery 
will receive bortezomib, temozolomide, and radiation all starting on day 1 (+/- 2 days) of 
study.  Day 1 of the study must be no sooner than 2 weeks from surgery and no longer than 6 
weeks after surgery, followed by bortezomib and temozolomide after completion of 
fractionated radiation for up to 24 additional cycles if no tumor growth is seen.  At this point, 
both bortezomib and temozolomide will be discontinued and patients will be monitored with 
routine MRI surveillance till progression.   
 
Patients will be treated with bortezomib 1.3 mg/ m² SQ on days 1, 4, 8, 11, 29, 32, 36, and 39 
and temozolomide 75 mg/m2 daily during radiation.  Bortezomib will be administered 
beginning on the first day of radiation with temozolomide.  External beam fractionated 
regional radiation will be given on consecutive week days at 200 cGy daily doses to a total 
dose of 6000 cGy (see Appendix 8.12).  Although the preferred two week rest period 
contrasts with the 4 week rest period used in the phase III radiation/temozolomide trial 
(Stupp, Mason et al. 2005),  we will attempt to shorten the rest period to 2 weeks in order to 
minimize treatment delay.  This shortened rest period has been safely used in a study 
examining the effect of upfront temozolomide and cis-retinoic acid and radiation (Butowski, 
Prados et al. 2005).  The 2-week rest period is also consistent with our current clinical 
practice.  However, if the patient has fatigue, bone marrow suppression, or other toxicities, 
the temozolomide rest period may be extended up to six weeks.  After a 2-6 week rest (for 
temozolomide and bortezomib) following completion of radiation therapy, temozolomide will 
be restarted at 150 mg/ m²/day day 1-5 of every 28 day cycle.  If this dose is tolerated, 
subsequent cycles will be given at 200 mg/ m²/day.  Bortezomib will be given at a dose of 1.3 
mg/m²on days 1, 4, 8, and 11 of a 28 day cycle commencing on the first day of 
temozolomide.  Temozolomide will not be increased greater than 200 mg/ m²/day.  No 
increases in bortezomib will be allowed.  Treatment with bortezomib and temozolomide will 
continue for 24 additional 28 day cycles following completion of radiation therapy if there is 
no evidence of progression.  At that time, both bortezomib and temozolomide will be stopped 
if there is no evidence of disease progression.  If unacceptable toxicities after the first 12 
cycles are observed per investigator’s discretion, the  bortezomib dosing schedule may be 
changed to 1.3 mg/m2 weekly for 3 weeks on and 1 week off, with the possibility of further 
reduction if necessary to 1.3 mg/m2biweekly.  Overall survival, 6-month progression free 
survival, and time to progression will be reported.  An interim analysis will be conducted on 
the first 10 patients.  This patient cohort will be monitored for unanticipated or unacceptable 
toxicities related to the combination of bortezomib and brain radiation, as well as focusing on 
delayed effects of radiation 4 weeks after the completion of radiation therapy.  Specifically, 
we will be looking for increased rates of brain hemorrhage, necrosis, and scalp wound 
healing problems.  Common adverse events such as myelosuppression or deep venous 
thrombosis (occurring in ~30% of patients with high-grade glioma (Robins, Won et al. 2006)) 
will also be carefully reviewed to determine whether they are related to the bortezomib 
combination.  Unless a clear causal relationship is demonstrated, such adverse advents will 
not be considered a toxicity due to bortezomib/RT combination therapy.   
 


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CLINICAL AND LABORATORY EVALUATIONS 
 
Pre-treatment Evaluations 
-A complete history and physical (to include height, weight, and BSA), vital signs 
(including blood pressure) and neurological examination (to include mental status, 
neurological function, and documentation of the patients Karnofsky performance 
status),  as well as neuro-imaging documentation of disease shall be performed on all 
patients within 21 days prior to  initiation of treatment.  In patients that have had 
immediate post-operative MRI scans, this will likely necessitate a repeat baseline 
MRI scan if treatment is initiated much greater than 21 days after resection. 
 
-Pre-study laboratory tests must include CBC with differential and platelets, serum 
creatinine, BUN, total bilirubin, SGOT, SGPT, serum electrolytes (including Na, Cl 
and K),PT, PTT, INR, glucose, albumin, alkaline phosphatase, calcium, total protein, 
urine test and creatinine clearance (calculated), anti-convulsant levels if applicable, 
and a serum pregnancy test for women of childbearing potential. Pre-study 
laboratory tests must be obtained within 14 days of initiation of   treatment.  Any 
abnormal pre-study laboratory tests must be rechecked within 48 hours of initiating 
therapy. 
 
- Documentation of tumor diagnosis. Following registration, slides from the pre-
registration biopsy must be submitted to UCLA for review. 
 
- Unstained paraffin block or slides from surgical samples:  A paraffinized tumor 
block must be obtained in all study patients from the surgery in which frozen tissue 
was collected, and in those patients who will be undergoing resection at time of 
treatment failure and during the follow-up period.  If such a tumor block cannot be 
obtained then 1 H & E stained slide and 20 unstained paraffin slides may be 
submitted instead.  Collection of an unstained paraffin block is optional in the 
follow-up part of the trial.  The paraffin block/slides will be used for MGMT 
methylation analysis and IDH1 genotyping.   
 
-Frozen surgical samples:  A frozen tumor block sample will be obtained in all study 
patients at the time of surgery, and in those patients who will be undergoing 
resection at time of treatment failure and during the follow-up period.  Collection of 
frozen tissue is optional in the follow-up part of the trial.  Frozen tissue will be used 
to verify MGMT methylation and IDH1 genotyping and for correlative studies. 
 
 
  
  
 
 
 
 
 
 
 
. 


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Evaluations During Treatment 
A. Evaluations to be obtained prior to and during the concomitant therapy with bortezomib, 
temozolomide and radiation: 
 
- 
Laboratory studies: CBC with differential and platelets will be performed weekly 
during radiation treatment. Creatinine, BUN, total bilirubin, SGOT, glucose, 
albumin, alkaline phosphatase, SGPT, calcium, total protein, serum electrolytes 
(including Na, Cl and K) will be performed every 2 weeks during radiation.   
 
 
- 
Plasma and serum collection prior to each treatment cycle on day 1 of each 28 
days treatment cycle. 
 
- 
Whole blood sample at initiation of treatment. 
 
 
 
Plasma Sample Collection and Preparation: 
 
Collect 5 mL of whole blood into a CTAD (B-D Cat #367947 Hemogard, 4.5 mL 
tube) blue top 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.  (Any contamination may invalidate the assay.)  Pipette the plasma 
specimen equally into plastic cryovials.  Do not transfer more than 1.5 mL into each 
tube.  Label tube with subject identification number, initials, and date of specimen 
collection. 
 
 
 
Serum Sample Collection and Preparation: 
 
Collect 5 mL of blood in one red top tube.  Immediately mix by inverting tubes 4 
times.  Complete the pre-printed labels with subject identification numbers, initials, 
and date of specimen collection.  Allow serum to clot for 30 minutes.  Spin at 2000 x 
g for 15 minutes to separate clot from serum. Pipette no more than 1.5 mL of serum 
specimen into plastic cryovials.  All specimens must be stored frozen at -20 C (or 
colder) until pickup. 
 


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Whole Blood Sample Collection and Preparation: 
Collect 8.5 mL blood in one PAXgene Blood DNA tube. 
 
1. 
Ensure that the PAXgene Blood DNA Tube is at room temperature (18-
25°C)prior to use and properly labeled with patient identification. 
 
2. 
The PAXgene Blood DNA Tube should be the last tube drawn. 
 
3.  
After blood collection, gently invert the PAXgene Blood DNA Tube 8 - 10 
times. 
 
4. 
Freeze PAXgene Blood DNA Tubes upright in a wire rack or horizontally in a 
plastic bag at -20 C (or colder).Do not freeze tubes upright in a Styrofoam® 
collection tray as this may cause the tubes tocrack. 
 
- 
A neurologic exam must be performed every two weeks during radiation therapy, 
to include: the patient’s Karnofsky performance status, neurological function, and 
mental status.   A general physical exam must also be performed every two weeks 
during radiation, to include:  examination of the skin within the treatment portal  
And evaluation for adverse events  These adverse events will be documented in 
the medical record, on the Flow sheet CRF, and reported to the principal 
investigator. Adverse events in subsequent cycles will be reported prior to the 
beginning of each cycle.  Height, weight, and BSA must be evaluated prior to 
each cycle. 
 
- 
MRI of the brain with and without gadolinium contrast is required within 21 days 
of Day 1 of the study. A postoperative MRI scan within 96 hours of surgery is 
also preferred.   
 
 
Evaluation during the radiation therapy:  
Procedures 
Prior to 
Treatment 
Every week 
Every  
2 weeks 
Every  
4 weeks 
At week 
6 
History, physical exam, 
height/weight  
X g 
 
X 
X 
X 
Neurologic Evaluation 
X g 
 
X 
X 
X 
Routine blood test 
Xa 
X 
 
X 
X 
Urine test 
X 
 
 
 
 
Research blood testf 
Xf 
 
 
X 
 
MRI head  
X h 
 
 
 
 
Pregnancy test 
Xb 
 
 
 
 
Pathology slides/frozen tissue  
X 
 
 
 
 
Study Treatment with 
Bortezomibd 
 
X 
Days 1, 4, 8, 11, 
29, 32, 36, 39 
 
 
 
Study Treatment with 
Temozolomidec 
 
X 
Days 1 - 42 
 
 
 
Radiation therapye 
 
X  
for 6 weeks 
 
 
 


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a Must be obtained within 14 days prior to starting treatment (weekly during radiation therapy). 
b for female patients of childbearing potential 
cTemozolomideDay 1 –42 during radiation therapy.  
dBortezomibon day 1, day 4, day 8 , day 11, day 29, day 32, day 36 and day 39 during radiation therapy. 
e Radiotherapy will be administered in 2Gy/day fractions delivered 5 days per week to a total dose of  60Gy over a six week period. 
fResearch blood test (on day 1 of a 28 day treatment cycle.) 
g Must be obtained within 14 days prior to treatment and every 2 weeks during radiation therapy 
h Must be obtained within  21 days of Day 1 of the study.  
 
B. Evaluations to be obtained after completion of radiation, during maintenance phase with 
bortezomib and temozolomide: 
 
- 
In general, a cycle is defined as a four-week interval starting from the first 
bortezomib/temozolomide dose given post-radiation.  If temozolomide is started 
first (if, for example, bortezomib is delayed because of peripheral neuropathy), 
wait to begin bortezomib until day 1 of the next four-week cycle.  Always begin 
bortezomib on day 1 of a cycle, never mid-cycle. 
 
- 
CBC with differential and platelets, creatinine, BUN, total bilirubin, SGOT, 
glucose, albumin, alkaline phosphatase, SGPT, calcium, total protein, and serum 
electrolytes (including Na, Cl and K) must be performed on days 21 and 28 (+/- 3 
days). If cycle is held for any reason, labs must be repeated again before cycle 
initiation if labs greater than 3 days from Day 1.  
 
- 
A neurologic exam must be performed every two weeks during radiation therapy 
and then every four weeks after radiation is completed (prior to the start of each 
new cycle). The exam must include: patient’s Karnofsky performance status, 
neurological function, and mental status.  A general physical exam must also be 
performed every four weeks after radiation is completed, to include:  height, 
weight, BSA, and evaluation for any adverse events.  Adverse events will be 
reported prior to the beginning of each cycle. 
 
 
- 
MRI of the brain with and without gadolinium contrast is required within 21 days 
of Day 1 of the study.  Then MRI will be performed 2 weeks 7 days after 
completion of radiation, and then every 8 weeks 7 days.  CT scanning with and 
without contrast may be substituted if an MRI is medically contraindicated. 
 
 
Evaluation to be Obtained During Bortezomib and Temozolomide after radiation 
Studies 
Day 1 
Day 21 
Day 29 
History, physical exam, height/weight, toxicity 
X 
 
X 
Neurologic Evaluation 
X 
 
X 
Routine blood test 
X 
X 
X 
Research blood test a 
X 
 
X 
MRI head b 
 
 
 
Temozolomide 
X   
Days 1 – 5 
 
X 
Bortezomib 
X    
Days 1, 4, 8, 11 
 
X 
aResearch blood test on day 1 of a 28 day treatment cycle. 
b MRI will be done 2 weeks after the end of the radiation therapy, then every 8 weeks. 
 


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- 
All relevant information regarding drug doses, concomitant medications and 
doses, measurable lesions, tumor response, laboratory examinations, and 
treatment-related toxicities shall be documented in the patient’s medical record 
and case report form flow sheets. 
 
- 
All patients will be followed for survival.  Patients who progress will be followed 
for survival every 4 months.  Patients who complete therapy and do not progress 
should be followed every 2 months for 12 months, every 3 months for the next 12 
months, every 4 months for the next 12 months, and then every 6 months until 
progression is determined.  They should then be followed for survival every 4 
months.  Patients will be asked to provide pathology slides and frozen tissue if 
they undergo elective surgery during the follow-up period.  Collection of an 
unstained paraffin block and frozen tissue is optional in the follow-up part of the 
trial.  Subjects will need to sign a separate consent form if they agree to donate the 
tissue samples. 
 
- 
If patients remain on study drug for greater than one year, the study evaluations 
for neurologic exam and physical exam may be changed to every 8 weeks.   
 
Central Review of MRI Scans 
 
 
 
 
 
 
Post-Treatment Evaluations  
 
Patients taken off study due to unacceptable toxicities or completion will be followed with a 
brain MRI at a minimum of every 2 months until progression is determined, and a 
neurological examination at a minimum of every 4 months.   
 
A study flow chart is provided in section 0. 
 
3.2 Selection of Patients 
The total number of patients to be enrolled on this study is: 50.  Enrollment is defined as the 
first day of VELCADE treatment (i.e., Day 1 of Cycle 1). 
 
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. 
 
3.2.1 Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
 Voluntary written informed consent obtained before performance of any study-related 
procedure not part of normal medical care, with the understanding that consent may be 
withdrawn by the subject at any time without prejudice to future medical care.  All 


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patients must sign an informed consent approved by the Institutional Review Board 
indicating that they are aware of the investigational nature of this study.  Patients must 
also sign an authorization for the release of their protected health information.  
 Female subject is post-menopausal for at least 1 year before the Screening visit, surgically 
sterilized, or if they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time,(i.e., a hormonal contraceptive, intra-uterine device, 
diaphragm with spermicide, condom with spermicide, or abstinence) from the time of 
signing the informed consent through 30 days after the last dose of study treatment, OR 
agree to completely abstain from heterosexual intercourse. 
 Male subject even if surgically sterilized (ie, status postvasectomy), whoagrees to practice 
effective barrier contraception during the entire study treatment period and through 30 
days after the last dose of study treatment, or agree to completely abstain from 
heterosexual intercourse. 
 Patients will have a histologically proven intracranial glioblastoma multiforme (GBM) or 
gliosarcoma (GS).  This includes treatment-naïve patients with prior tissue diagnoses of 
lower grade gliomas that have been upgraded to GBM after repeat resection. 
 Cranial MRI or contrast CT must have been performed within 21days of study entry.  The 
use of MRI rather than CT is preferred.  The same type of scan, i.e., MRI or CT must be 
used throughout the period of protocol treatment for tumor measurement.  If the surgical 
procedure was a resection, cranial MRI or contrast CT performed within 96 hours of 
resection is preferred, but not required.  Patients without measurable or assessable disease 
are eligible. 
 Patients must begin partial brain radiotherapy no sooner than 2 weeks and no later than 6 
weeks from the surgery in which tissue was collected.  Patients with GBM diagnosis from 
surgeries in which tissue was not collected will be eligible after repeat surgery is 
performed to collect tissue, as long as no treatment has been initiated prior to the surgery 
in which tissue was collected.  In this case, initiation of treatment must begin within three 
to six weeks from the last surgery.   Patients may have radiotherapy administered at 
outside facilities according to the specified guidelines (Appendix 8.12). Radiotherapy 
must be given by external beam to a partial brain field in daily fractions of 2.0 Gy, to a 
planned total dose to the tumor of 60.0 Gy in accordance with Appendix 8.12  
Stereotactic radiosurgery and brachytherapy will not be allowed. 
 Patients must be willing to forego other drug therapy against the tumor while being 
treated with bortezomib, temozolomide, and radiation, and subsequently bortezomib and 
temozolomide. 
 Patients must be > 18 years old, and with a life expectancy > 8 weeks. 
 Patients must have a Karnofsky performance status of > 60. 
 Patients must have adequate bone marrow function (WBC > 3,000/µl, ANC > 1,500/mm3, 
platelet count of > 100,000/mm3, and hemoglobin > 10 gm/dl) and the test must be 
performed within 14 days prior to registration.  Eligibility level for hemoglobin may be 
reached by transfusion. 
 Patients must have adequate liver function (SGOT < 2.5 times ULN and bilirubin < 1.5 
times ULN) and the test must be performed within 14 days prior to registration. 
 Patients must have adequate renal function (creatinine < 1.5 mg/dL) before starting 
therapy and the test must be performed within 14 days prior to registration.  


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 Serum sodium >130 mmol/L 
 
3.2.2 Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study. 
 Patient has a platelet count of  <100 109/L  within 14 days before enrollment. 
 Patient has an absolute neutrophil count of <1.5  109/L  within 14 days before 
enrollment. 
 Patient has a calculated or measured creatinine clearance of  <20 mL/minute within 
14 days before enrollment. 
 Patient has Grade 2 peripheral neuropathy within 14 days before enrollment. 
 Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled angina, 
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities. Prior to study entry, any ECG 
abnormality at screening has to be documented by the investigator as not medically 
relevant. 
 Patient has hypersensitivity to bortezomib, boron, or mannitol. 
 Female subject is pregnant or breast-feeding.  Confirmation that the subject is not 
pregnant must be established by a negative serum -human chorionic gonadotropin (-
hCG) pregnancy test result obtained during screening.  Pregnancy testing is not required 
for post-menopausal or surgically sterilized women.  Women with reproductive potential 
must practice adequate contraception for the duration of the study. The anti-proliferative 
effects of the investigational agent may be detrimental to the developing fetus or nursing 
infant. 
 Participation in clinical trials with other investigational agents not included in this trial, 
within 14 days of the start of this trial and throughout the duration of this trial. 
 Serious medical or psychiatric illness likely to interfere with participation in this clinical 
study including, but not limited to, ongoing or active infection requiring IV antibiotics,  
psychiatric illness/social situations that would limit compliance with study requirements, 
or disorders associated with a significant immunocompromised state (HIV, SLE, etc.); 
 Diagnosed or treated for another malignancy within 3 years of enrollment, with the 
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of 
the skin, an in situ malignancy (such as cervical), or low-risk prostate cancer after 
curative therapy.  Patients must be in complete remission and off of all therapy for that 
disease for a minimum of 3 years.  
 Patients must not have received previous radiotherapy to the brain. 
 Patients must not have received cytotoxic drug therapy, non-cytotoxic drug therapy, or 
experimental drug therapy directed against the brain tumor.  Patients who received 
Gliadel wafers will be excluded.  Patients may have received or be receiving 
corticosteroids, AED’s, analgesics, and other drugs to treat symptoms or prevent 
complications. 
 Since VELCADE is partially metabolized by inducers of CYP450 3A4 such as Enzyme-
inducing  anti-epileptic drugs (EIAED), patients on EIAED must be transitioned to non-
EAIED at least 2 weeks prior to initiation of treatment. 


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 Patients must not have received previous radiotherapy to the brain. 
 
General Medical Concerns 
 Patients must not have any significant medical illnesses that in the investigator’s opinion 
cannot be adequately controlled with appropriate therapy or would compromise the 
patient’s ability to tolerate this therapy.  
 Patients receiving current, ongoing treatment with full-dose warfarin or its equivalent 
(i.e., unfractionated and/or low molecular weight heparin) are NOT excluded (see 1.2.2).  
However, since Velcade is weak inhibitor of CYP450 2C19, close monitoring of INR will 
be required. 
 Patients must not have any disease that will obscure toxicity or dangerously alter drug 
metabolism. 
 No viral hepatitis (hep B surface ag positive), or active hepatitis C infection. 
 History of stroke within the past 6 months.  
 
3.3 Study Treatments 
3.3.1 Clinical Trial Materials 
VELCADE (bortezomib) for Injection is a sterile lyophilized powder for reconstitution and is 
supplied in vials containing VELCADE and mannitol at a 1:10 ratio.  For example, vials 
containing 3.5 mg of VELCADE contain 35 mg of mannitol.   
 
Temozolomide (TEMODAR®) is commercially available, manufactured and distributed by 
Schering-Plough, Inc.  The oral capsules contain a white to light tan/light pink powder. The 
molecule is stable at acidic pH (<5), and labile at pH >7, hence TEMODAR can be 
administered orally. The prodrug, temozolomide, is rapidly hydrolyzed to the active 5-(3-
methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with 
hydrolysis taking place even faster at alkaline pH.  Each capsule contains either 5 mg, 20 mg, 
100 mg, or 250 mg of temozolomide. The inactive ingredients for TEMODAR Capsules are 
lactose anhydrous, colloidal silicon dioxide, sodium starch glycolate, tartaric acid, and stearic 
acid. Gelatin capsule shells contain titanium dioxide. The capsules are white and imprinted 
with pharmaceutical ink. 
 
TEMODAR 5 mg: green imprint contains pharmaceutical grade shellac, anhydrous ethyl 
alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, titanium 
dioxide, yellow iron oxide, and FD&C Blue #2 aluminum lake.  TEMODAR 20 mg: brown 
imprint contains pharmaceutical grade shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-
butyl alcohol, propylene glycol, purified water, ammonium hydroxide, potassium hydroxide, 
titanium dioxide, black iron oxide, yellow iron oxide, brown iron oxide, and red iron oxide.  
TEMODAR 100 mg: blue imprint contains pharmaceutical glaze (modified) in an 
ethanol/shellac mixture, isopropyl alcohol, n-butyl alcohol, propylene glycol, titanium 
dioxide, and FD&C Blue #2 aluminum lake. TEMODAR 250 mg: black imprint contains 
pharmaceutical grade shellac, anhydrous ethylalcohol, isopropyl alcohol, n-butyl alcohol, 
propylene glycol, purified water, ammonium hydroxide, potassium hydroxide, and black iron 
oxide. 
 
Radiation-see Appendix 8.11 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 40 of 86 Amendment 7 version dated February 11, 2014 
 
3.3.2 Preparation, Handling, and Storage of Drugs 
VELCADE (bortezomib) 
 
Vials containing lyophilized VELCADE for Injection should be stored according to the label 
requirements.  For the United States, store at USP Controlled Room Temperature which is 
25ºC (77ºF); excursions permitted from 15 to 30ºC (59 to 86ºF).  For Europe, do not store 
above 30ºC (86ºF).  To date, stability data indicate that the lyophilized drug product is stable 
for at least 18 months when stored under the recommended conditions. Stability studies are 
ongoing, and Millennium Pharmaceuticals, Inc. will notify the investigator should this 
information be revised during the conduct of the study. 
 
VELCADE is cytotoxic.  As with all cytotoxic drugs, caution is required when preparing and 
handling VELCADE solutions.  Cytotoxic drugs should only be handled by staff specially 
trained in the safe handling of such preparations. The use of gloves and other appropriate 
protective clothing is recommended.  In case of skin contact, wash the affected area 
immediately and thoroughly with soap and water for at least 15 minutes.  If product contacts 
eye, immediately flush eye thoroughly with water for at least 15 minutes.  Always contact a 
physician after any form of body contact. All materials that have been used for preparation 
should be disposed of according to standard practices. A log must be kept of all disposed 
materials. 
 
Drug is available in sterile, single use vials containing 3.5 mg of VELCADE.  Each vial of 
VELCADE for Injection should be reconstituted under a laminar flow biological cabinet 
(hood) within eight hours before dosing with 3.5 mL of normal (0.9%) saline for intravenous 
or 1.4 mL for subcutaneous (see below), Sodium Chloride Injection USP, so that the 
reconstituted solution contains VELCADE at a concentration of 1 mg/mL.  Prior to 
reconstitution the vials should remain in the cartons to protect them from light.  Dissolution is 
completed in approximately 10 seconds.  The reconstituted solution is clear and colorless, 
with a final pH of 5 to 6.  Reconstituted VELCADE should be administered promptly and in 
no case more than 8 hours after reconstitution.  All materials that have been used for 
preparation should be disposed of according to standard practices.  A log must be kept of all 
disposed materials. 
 
Bortezomib Destruction 
 
Investigational bortezomib (expired or end of study) should be destroyed on site according to 
the institution’s standard operating procedure.  Be sure to document removal and destruction 
on drug accountability logs. 
 
Temozolomide 
Tablets may be stored at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).  The 
commercial product has an expiration date on the label of the bottle. 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
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Drug administration and dosage schedule 
Administration and schedule of chemotherapy: 
 
RT Phase:  (Beginning 2-6 weeks post surgery) 
 
Bortezomib1.3 mg/ m² SQ on days 1, 4, 8, 11, 29, 32, 36, and 39 during the 6 weeks of 
radiation.If dosing has to be delayed for any reason (such as holidays), subsequent treatments 
must be at least 3 days after prior dose. 
 
Temozolomide75 mg/m2/day PO starting on Day 1 during radiation and continuing for 42 
consecutive days.  
External beam fractionated regional radiation will be given on consecutive week days at 200 
cGy daily doses to a total dose of 6000 cGy. 
 
Bortezomib 
1.3mg/ m² 
SQ 
Days 1, 4, 8, 11, 29, 32, 36, 39 x 6 weeks 
Temozolomide 75 mg/m2/day 
PO 
Day 1 x 42 consecutive days 
XRT 
200 cGy doses 
XRT Days Monday-Friday (total dose 6000 cGy) 
 
 
Maintenance Phase: (Beginning after a 2-6 week rest post XRT) 
Bortezomib 1.3 mg/ m² SQ will given on days 1, 4, 8, and 11 of a 28 day cycle commencing 
on the first day of temozolomide. Day 1dosing of any cycle can be delayed for any non-
toxicity reason (such as holidays) for up to 7 days, with the subsequent cycle starting no 
earlier than 28 days from the beginning of the delayed cycle.  Similarly, if day 4,8, or 11 
treatments need to be delayed for any non-toxicity related reason, then subsequent treatments 
must be at least 3 days after delayed dose. 
 
Temozolomide150 mg/m2/day day 1-5 of every 28 day cycle, increased to 200 mg/m2/day 
beginning in the second post RT cycle if no toxicities observed.  
 
Restaging with cranial MRI every 8 weeks, and continuing treatment for 24 additional 28 day 
cycles.  
 
1st Cycle 
 
 
 
Bortezomib 
1.3mg/ m² 
SQ 
Days 1, 4, 8, 11, of a 28 day cycle 
Temozolomide 
150 mg/m2/day 
PO 
 Day 1-5  of a 28 day cycle  
2nd Cycle 
 
 
 
Bortezomib 
1.3mg/ m2 
SQ 
Days 1, 4, 8, 11, of a 28 day cycle for 24 
additional cycles 
Temozolomide 
200 mg/m2/day 
PO 
 Day 1-5  of a 28 day cycle for 24 additional 
cycles 
 
** Temozolomide will not be increased greater than 200 mg/m2/day.  No increases in 
bortezomib above 1.3 mg/kg will be made.  
 
Patients will be treated with bortezomib 1.3 mg/m² SQ on days 1, 4, 8, 11, 29, 32, 36, and 39  
and temozolomide 75 mg/m²/day during radiation for 42 consecutive days.   If there is 
myelotoxicity (ANC<1.5 or Plt<100) as determined on weekly blood draws, both 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 42 of 86 Amendment 7 version dated February 11, 2014 
 
temozolomide and bortezomib will be held until (ANC>1.5 or Plt >100). One dose reduction 
will be allowed of bortezomib to 1.0 mg/ m² for the duration of the radiation phase.  No dose 
reductions in temozolomide are permitted.  If lower dose results in myelotoxicity (ANC<1.5 
or Plt <100), treatment will be held until counts have recovered and resumed at this same 
lower dose.  External beam fractionated regional radiation will be given on week days at 200 
cGy doses to a total dose of 6000 cGy as specified in Appendix 8.12.  The first post-radiation 
temozolomide cycle should be synchronized to within +/- two days of a bortezomib 
treatment.  After a 2-6 week rest (two weeks preferred, but up to six weeks acceptable 
depending on toxicity) from temozolomide and bortezomib, following completion of 
radiation therapy, temozolomide will be restarted at 150 mg/m²/day for 5 days out of every 
28.  If there is myelotoxicity, dose reduction of both drugs will be planned as in below table.  
If the initial starting level is tolerated, subsequent cycles will be given at 200mg/m²/day.  
Bortezomib at 1.3 mg/m² will given on days 1, 4, 8, and 11 of a 28 day cycle commencing on 
the first day of temozolomide.  Temozolomide will not be increased greater than 200 mg/ 
m²/day.  Bortezomib will not be increased greater than 1.3 mg/m²/day.  Assuming that the 
dosages of bortezomib and temozolomide are well tolerated, and no deterioration or treatment 
related toxicity sufficient to terminate study participation occurs, patients will then undergo 
clinical and radiographic tumor restaging and continue treatment for 24 additional 28 day 
cycles.  If unacceptable toxicities after the first 12 cycles are observed per investigator’s 
discretion, the bortezomib dosing schedule may be changed to 1.3 mg/m2 weekly for 3 weeks 
on and 1 week off, with the possibility of further reduction if necessary to 1.3 mg/m2 
biweekly. 
 
VELCADE Administration 
 
Bortezomib will be given at 1.3 mg/m² SQ on days 1, 4, 8, 11, 29, 32, 36, and 39 during the 6 
weeks of radiation.  Bortezomib will be given at 1.3 mg/m²   on days 1, 4, 8, and 11 of a 28 
day cycle commencing on the first day of temozolomide for up to 24 cycles.  Drug will be 
administered only to eligible patients under the supervision of the investigator or identified 
sub-investigator(s).  Patients may be treated on an out-patient basis, if possible.   
 
The drug will be prepared under the supervision of a pharmacist, or appropriately qualified 
and trained personnel.  The amount (in mg) of drug to be administered will be determined 
based on body surface area.  Body surface area is to be calculated based on body weight 
using a standard nomogram (see section 8.3).  The dose should be calculated using patient’s 
baseline weight.  If a patient experiences a notable change in weight (loss or gain of 10%) , 
then the patient’s dose should be recalculated at that time and will become the new baseline 
weight.   
 
There must be at least 72 hours between each dose of bortezomib. 
INTRAVENOUS AND SUBCUTANEOUS ROUTE OF ADMINISTRATION HAVE 
DIFFERENT RECONSTITUTED CONCENTRATIONS. CAUTION SHOULD BE USED 
WHEN CALCULATING THE VOLUME TO BE ADMINISTERED. 
SUBCUTANEOUS ADMINISTRATION:  
Drug is available in sterile, single use vials containing 3.5 mg of bortezomib.  Each vial of 
bortezomib for Injection should be reconstituted under a laminar flow biological cabinet 
(hood) within eight hours before dosing with 1.4 mL of normal (0.9%) saline, Sodium 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 43 of 86 Amendment 7 version dated February 11, 2014 
 
Chloride Injection USP, so that the reconstituted solution contains bortezomib at a 
concentration of 2.5 mg/mL for subcutaneous administration. 
 
Subcutaneous Administration Precautions:  
 The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required.  
Caution should be used in calculating the dose to prevent overdose.  
 When administered subcutaneously, sites for each injection (thigh or abdomen) 
should be rotated.   
 New injections should be given at least one inch from an old site and never into areas 
where the site is tender, bruised, erythematous, or indurated.  
 If local injection site reactions occur following bortezomib administration 
subcutaneously, a less concentrated bortezomib solution (1 mg/mL instead of 2.5 
mg/mL) may be administered subcutaneously.  Alternatively, the IV route of 
administration should be considered. 
 In clinical trials of bortezomib IV, local skin irritation was reported in 5% of patients, 
but extravasation of bortezomib was not associated with tissue damage. In a clinical 
trial of subcutaneous VELCADE, a local reaction was reported in 6% of patients as an 
adverse event, mostly redness. 
 
Temozolomide Admininstration 
 
Temozolomide will be given at 75 mg/ m²/day during radiation for 42 consecutive days.  
After a short holiday interval, temozolomide will resume at 150 mg/ m²/day for 5 days out of 
every 28, and planned to be increased to 200 mg/ m²/day.  Temozolomide is rapidly and 
completely absorbed after oral administration; peak plasma concentrations occur in 1 hour. 
Food reduces the rate and extent of temozolomide absorption. Mean peak plasma 
concentration and AUC decreased by 32% and 9%, respectively, and Tmax increased 2-fold 
(from 1.1 to 2.25 hours) when temozolomide was administered after a modified high-fat 
breakfast.  Therefore, patients will be instructed to take temozolomide on an empty stomach, 
defined as not eating 1 hour before or 1 hour after drug administration.   
 
3.3.3 Dose Modification and Delay 
Radiation phase: 
Temozolomide 
No dose reductions in temozolomide are allowed during the concomitant phase; however, 
dose interruptions or discontinuation may occur based on toxicity. The TEMODAR dose 
should be continued throughout the 42-day concomitant period if all of the following 
conditions are met: absolute neutrophil count ≥1.5 x 109/L, platelet count ≥100 x109/L, 
common toxicity criteria (CTC) non-hematological toxicity no greater then Grade 1 (except 
for alopecia, nausea, and vomiting), and no greater than Grade 2 for fatigue. During treatment 
a complete blood count including differential and platelets should be obtained weekly. 
Temozolomide dosing should be interrupted or discontinued during concomitant phase 
according to the hematological and non-hematological toxicity criteria as noted in Table 5. 
(Note: If temozolomide is interrupted or discontinued, bortezomib will be interrupted or 
discontinued as well.)  PCP prophylaxis is required during the concomitant administration of 
TEMODAR and radiotherapy, and should be continued in patients who develop 
lymphocytopenia until recovery from lymphocytopenia (CTC Grade 1). 
 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 44 of 86 Amendment 7 version dated February 11, 2014 
 
 
 
Table 5 
Temozolomide Dosing interruption or Discontinuation During Concomitant 
Radiotherapy and Temozolomide 
Toxicity 
TMZ Interruption a 
TMZ Discontinuation 
Absolute Neutrophil Count 
≥0.5 and <1.5 x 109/L 
<0.5 x 109/L 
Platelet Count 
≥10 and <100 x 109/L 
<10 x 109/L 
CTC Non-hematological 
toxicity (except for alopecia, 
nausea, vomiting, fatigue, 
and constipation) 
CTC Grade 3 or intolerable 
Grade 2and at the 
investigators’ discretion. 
CTC Grade 4 
a Treatment with concomitant TMZ may be continued when all of the following conditions 
are met: absolute neutrophil count ≥1.5 x 109/L; platelet count ≥ 100 x 109/L; CTC non-
hematological toxicity ≤ Grade 2 (except for alopecia, nausea, vomiting, fatigue, and 
constipation). 
TMZ- temozolomide; CTC = Common Toxicity Criteria 
 
Bortezomib 
 
If TMZ (and bortezomib) need to be interrupted per criteria in Table 5,  resumption of TMZ 
at 75 mg/ m² and bortezomib at a lower dose (-1 dose reduction) will be allowed when 
toxicity recovers to an absolute neutrophil count ≥1.5 x 109/L,  platelet count ≥100 x109/L, or 
CTC non-hematologic toxicity ≤ Grade 2 (see Table 5).   If counts require TMZ 
discontinuation, then bortezomib will also be discontinued for the duration of the radiation 
phase.   
 
Radiation Phase:   
Dose Level 
Bortezomib 
(days 1, 4, 8, 11, 29, 32, 
36, and 39) 
Temozolomide 
(daily x 42 d) 
-1 
1.0 mg/m2 
75 mg/m2 
Starting 
1.3 mg/m2 
75 mg/m2 
 
Maintenance (Post-radiation) phase: 
 
Temozolomide and Bortezomib 
 
Dosage of temozolomide in Cycle 1 (maintenance) is 150 mg/ m² once daily for 5 days 
followed by 23 days without treatment.  At the start of Cycle 2, the dose is escalated to 200 
mg/ m², if the CTC non-hematologic toxicity for Cycle 1 is Grade 2 (except for alopecia, 
nausea, vomiting, fatigue, or constipation), absolute neutrophil count (ANC) is ≥1.5 x 109/L, 
and the platelet count is ≥100 x 109/L.  The dose remains at 200 mg/ m² per day for the first 5 
days of each subsequent cycle except if toxicity occurs.  If the dose was not escalated at 
Cycle 2, escalation should not be done in subsequent cycles.  During treatment, a complete 
blood count with differential and platelets should be obtained on Day 22 (21 days after the 
first dose of TEMODAR) or within 72 hours (± 3 days) of that day, and weekly until the 
ANC is above 1.5 x 109/L (1500/µL) and the platelet count exceeds 100 x 109/L 
(100,000/µL). 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 45 of 86 Amendment 7 version dated February 11, 2014 
 
 
The next cycle of TEMODAR should not be started until the ANC and platelet count exceed 
these levels. Delay in treatment cannot exceed 4 weeks, and tumor must be stable.  Dose 
reductions during the next cycle should be based on the lowest blood counts and worst non-
hematologic toxicity during the previous cycle. Dose reductions or discontinuations during 
the maintenance phase should be applied according to Tables 6 and 7.  If further dose 
reductions are required, schedule should follow Table 9. 
 
Temozolomide and bortezomib dosage will be recalculated during maintenance phase if there 
is a weight loss or gain of  ≥10% of baseline weight.  If this is required, then this weight used 
to recalculate the new dose will then be taken as the new baseline. 
 
 
 
 
 
 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 46 of 86 Amendment 7 version dated February 11, 2014 
 
 
Table 9:  Maintenance (Post-radiation) (28 day cycle): 
Dose Levela 
Bortezomib 
(days 1, 4, 8, and 11) 
Temozolomide 
(day 1) 
-3 
1.0 mg/m2 
75  mg/ m2 
-2 
1.0 mg/m2 
100 mg/ m2 
-1 
1.3 mg/m2 
100 mg/m2 
Starting 
1.3 mg/m2 
150 mg/m2 
+1 
1.3 mg/m2 
200 mg/m2 
a Except for neuropathic pain, see Table 3.1 (bortezomib reduced to 0.7 mg/m2) 
 
Before each drug dose, the patient will be evaluated for possible toxicities that may have 
occurred after the previous dose(s).  Toxicities are to be assessed according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 (see section 8.6). 
 
All previously established or new toxicities observed any time, with the exception of 
neuropathic pain and peripheral sensory neuropathy, are to be managed as follows: 
 
If the patient experiences febrile neutropenia, a Grade 4 hematologic toxicity (including a 
platelet count <25  109/L) or any  Grade 3 non-hematologic toxicity considered by the 
investigator to be related to TMZ or VELCADE, then drugs are to be held. 
 
For any ≥ Grade 3 non-hematologic toxicities, VELCADE is to be held for up to 2 weeks 
until the toxicity returns to Grade 1 or better. 
 
Dose interruption or study discontinuation is not required for lymphopenia of any grade.   


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 47 of 86 Amendment 7 version dated February 11, 2014 
 
 
If, after VELCADE has been held, the toxicity does not resolve, as defined above, then drug 
must be discontinued. 
 
Patients who experience VELCADE-related neuropathic pain and/or peripheral sensory 
neuropathy are to be managed as presented in Table 3.1 Management of Patients with 
VELCADE-Related Neuropathic Pain and/or Peripheral Sensory Neuropathy. 
 
Table 3-1 
Management of Patients with VELCADE Related Neuropathic Pain 
and/or Peripheral Sensory or Motor Neuropathy 
 
Recommended Dose Modification for VELCADE related Neuropathic Pain and/or Peripheral Sensory or Motor 
Neuropathy  
Severity of Peripheral Neuropathy  
Signs and Symptoms  
Modification of Dose and Regimen  
Grade 1 (paresthesias, weakness and/or loss of 
reflexes) without pain or loss of function  
No action  
Grade 1 with pain or Grade 2 (interfering with  
function but not with activities of daily living)  
Reduce VELCADE by one dose level* If toxicity 
persists reduce by another one dose level. * 
Grade 2 with pain or Grade 3 (interfering with  
activities of daily living) 
Withhold* VELCADE therapy until  
toxicity resolves.  
When toxicity resolves reinitiate with  
a reduced dose of VELCADE at 0.7 mg.m2 and 
change treatment schedule to once per week.* If 
toxicity recurs, change treatment schedule to once 
every two weeks. * 
Grade 4 (Sensory neuropathy which is disabling 
or motor neuropathy that is life threatening or 
leads to paralysis)  
Discontinue VELCADE  
Grading based on NCI Common Terminology Criteria CTCAE v3.0    
NCI Common Terminology Criteria website - http://ctep.info.nih.gov/reporting/ctc.html  
ADL = activities of daily living 
*Key: 
Reduce by one dose level: VELCADE dose reduction from 1.3 to 1.0, or 1.0 to 
0.7mg/m2/dose. 
 
Hold:   
Interrupt VELCADE until the toxicity returns to Grade 1 or 
better. 
 
Schedule change:  Schedule change from VELCADE twice per week (Days 1, 4, 8 and 11 on a 
Q4W cycle) to once per week (Days 1, 8, and 15 on a Q4W cycle).   
 
Change from once per week to once every two weeks (Days 1, 15 on a Q4W 
cycle).  
 
The neurotoxicity-directed questionnaire (see section 8.8) is a useful tool for determining the 
presence and intensity of neuropathic pain and/or peripheral neuropathy from the patient’s 
perspective.  Neuropathic symptoms are more prominent than abnormalities on the clinical 
examination.  After the patient completes the neurotoxicity-directed questionnaire, the 
questionnaire should be reviewed to assist with the evaluation of the onset and intensity of 
peripheral neuropathy and other neurotoxicities that may possibly require intervention or 
dose modification. 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 48 of 86 Amendment 7 version dated February 11, 2014 
 
 
Patients with mild hepatic impairment (bilirubin ≤ 1.5  ULN) do not require a starting dose 
adjustment.  Please note that patients with bilirubin levels > 1.5 ULN are excluded from 
enrollment in this protocol.  If a patient develops moderate or severe hepatic impairment with 
bilirubin ≥ Grade 2 (> 1.5 -3.0 X ULN) while on study, the investigator should hold 
Bortezomib until the toxicity returns to < Grade 2. Restarting Bortezomib at the next lower 
dosed level could be considered at the Investigator’s discretion and following exclusion of  
Bortezomib-induced liver impairment and careful consideration of liver disease due to other 
causes, such as, but not limited to, active infection and multiple myeloma-related liver 
disease. 
 
3.3.4  
Treatment Assignment 
not applicable 
 
3.3.5  Blinding, Packaging, and Labeling 
VELCADE will be supplied in vials as open-label stock.  Both the box label and vial label 
will fulfill all requirements specified by governing regulations.   
Temozolomide will be obtained through the patient’s pharmacy. 
3.3.6 Concomitant Treatment 
Concurrent Therapy 
 Other Anti-cancer or Experimental Therapy: No other anti-cancer therapy (including 
chemotherapy, hormonal treatment or immunotherapy) of any kind is permitted during 
the study period.  No other drug under investigation may be used concomitantly with 
the study drug.  Patients are not allowed to participate concurrently in any other clinical 
study. 
 Corticosteroids:Should be used in the smallest dose to control symptoms of cerebral 
edema and mass effect, and discontinued if possible. 
 Anti-seizure medications: Should be used as necessary, however, since VELCADE is 
partially metabolized by inducers of CYP450 3A4 such as Enzyme-inducing  anti-
epileptic drugs (EIAED), patients on EIAED must be transitioned to non-EAIED at 
least 2 weeks prior to initiation of treatment. 
 Antiemetics:  Investigators will use their own discretion with regard to the appropriate 
treatment of nausea or vomiting. 
 Anticoagulants:  Patients who require treatment with full-dose warfarin or its 
equivalent (i.e., unfractionated and/or low molecular weight heparin) will NOT be 
removed from the study.  Frequent monitoring of the INR is recommended. 
 Growth Factors:  Routine prophylactic use of G-CSF in the first course of therapy is 
not permitted, and secondary prophylaxis with G-CSF in subsequent courses is not 
generally recommended.  Use of GM-CSF is not permitted at any time.  However, 
prophylactic administration of G-CSF in a patient who is experiencing recurrent 
difficulties with neutropenia in subsequent cycles, or therapeutic use in patients with 
serious neutropenic complications such as tissue infection, sepsis syndrome, fungal 
infection, etc., may be considered at the investigator's discretion. 
 Other Concomitant Medications: Therapies considered necessary for the patient's well 
being may be given at the discretion of the investigator.  On the day of VELCADE 


VELCADE (bortezomib) for Injection 
 
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CONFIDENTIAL 
Page 49 of 86 Amendment 7 version dated February 11, 2014 
 
administration, patients should not take any vitamin supplements such as Vitamin C, 
alpha lipoic acid, any antioxidant, or green tea.  Other concomitant medications should 
be avoided except for analgesics, chronic treatments for concomitant medical 
conditions, or agents required for life-threatening medical problems. All concomitant 
medications (prescription and OTC) must be recorded in the medical record and the 
case report forms.    
 Potential drug interactions: Bortezomib has the ability to inhibit a variety of liver 
metabolic enzymes in vitro. The clinical impact of this inhibition in human taking 
drugs metabolized by these enzymes is unknown. Therefore, all patients enrolled onto 
this trial who are taking concomitant medications that are known to be metabolized by 
the liver should be closely observed for side-effects of these concomitant medications. 
(see Appendix 8.13 for the list of those medications) 
 Febrile neutropenia:  May be managed according to the local institution’s Infectious 
Disease guidelines.  Measures may include appropriate laboratory testing, including 
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. 
 Pneumocystis Pneumonia (PCP) prophylaxis:  
Since patients with malignant gliomas are at increased risk of developing PCP, 
especially if they are on corticosteroids, prophylaxis for PCP may be considered per 
institutional practice. 
 Any investigational agent other than VELCADE is not permitted. 
 
3.3.7 Treatment Compliance 
 
All drug will be administered to eligible patients under the supervision of the investigator or 
identified sub-investigator(s).  The pharmacist will maintain records of drug receipt (if 
applicable), drug preparation, and dispensing, including the applicable lot numbers, patients’ 
height, body weight, and body surface area (see section 8.3), and total drug administered in 
milliliters and milligrams.  Any discrepancy between the calculated dose and dose 
administered, and the reason for the discrepancy, must be recorded in the source documents. 
 
3.4 Duration of Treatment and Patient Participation 
 
Patients will receive up to 24 28 day cycles of temozolomide and bortezomib after radiation 
therapy.  All patients will be followed for survival.  Patients who progress will be followed 
for survival every 4 months.  Patients who complete therapy and do not progress should be 
followed every 2 months for 12 months, every 3 months for the next 12 months, every 4 
months for the next 12 months, and then every 6 months until progression is determined.  
They should then be followed for survival every 4 months. Patients taken off study because 
of unacceptable toxicities will be followed up every 2 months until the toxicity is resolved or 
progression is determined by MRI.   
 
3.5 Termination of Treatment and/or Study Participation 
 
Patients will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care.  The investigator also has the right to 
withdraw patients from the study for any of the following reasons: 
 Intercurrent illness 


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 Occurrence of an unacceptable adverse event 
 A treatment cycle delay or VELCADE and TMZ interruption of >4 weeks or missing 
three of four VELCADE doses within a treatment cycle because of toxicity 
 Patient request 
 Protocol violations 
 Non-compliance 
 Administrative reasons 
 Failure to return for follow-up 
 General or specific changes in the patient’s condition unacceptable for further 
treatment in the judgment of the investigator 
 Progressive disease at any time 
 
At the time of withdrawal, patients must have a physical exam, a neurological exam, urine 
tests and routine blood tests. The primary reason for a patient’s withdrawal from the study is 
to be recorded in the source documents. 
 
3.6 Efficacy, Pharmacodynamic/Pharmacogenomic/Correlative studies, and Safety 
Measurements 
 
3.6.1 Efficacy Measurements 
3.6.1.1 Primary Efficacy Variables: 
Overall Survival 
 
3.6.1.2 Secondary Efficacy Variables: 
12-month survival and median time to tumor progression tumor response as assessed 
by MRI and neurologic exam, toxicity. 
 
The patients will have a brain MRI evaluation of response and progression every 8 
weeks, starting from the day 56 scan obtained 2 weeks after completion of radiation 
and daily temozolomide.  MRI  assessment will be conducted on a 7-point scale.  This 
scale is expected to be more useful in this study because many newly-diagnosed 
patients are likely not to have evaluable disease due to gross total resections.  A -2 or -
3 assessment will be taken as progression.  Determination of whether progression 
occurs based on the day 56 scan will take into account the untreated window between 
baseline MRI and day of 1 of the study. 
 
complete resolution of tumor: 3 
tumor definitely smaller: 2  
tumor probably smaller: 1  
tumor unchanged: 0  
tumor probably worse: -1  
tumor definitely worse: -2  
new lesion: -3 
 
Neurological Exam: Although not used for determining response, it is useful to 
evaluate improvement in the neurologic exam that should coincide with objective 


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measurement of tumor size. 
 
 
+2 
Definitely better 
+1 
Possibly better 
  0 
Unchanged 
-1 
Possibly worse 
-2 
Definitely worse 
 B 
Baseline 
 
Performance Status, Neurological Function, and Mental Status: Patients will be 
graded according to Karnofsky Performance Status (see Appendix 8.2), 
Neurological Function and Mental Status. 
 
Time to Treatment Failure: From date of registration to the date of first observation of 
progressive disease, non-reversible neurologic progression, or permanently 
increased steroid requirement (applies to stable disease only), death due to any 
cause, or early discontinuation of treatment. 
 
Time to Death: From date of registration to date of death due to any cause. 
 
Molecular Analysis: Pre-treatment biomarker data (MGMT promoter methylation and 
IDH1 
genotype) 
will 
be 
analyzed 
and 
descriptive 
statistics 
will 
be 
generated. Analyses of a graphical nature comparing the biomarker data with the best 
overall response (CR, PR, SD, PD) are also planned. 
 
3.6.2 Pharmacokinetic/Pharmacodynamic/Pharmacogenomic/Correlative Studies 
  
 
  
 
 
  
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
  
 
 


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3.6.3 Safety Measurements 
Toxicity/safety: Patients will be assessed using CTC 3.0 for Grade 3 or greater 
treatment related non-hematologic toxicities.   
 
4 ADVERSE EVENTS 
All serious adverse events (SAEs) (regardless of expectedness, causality, and whether 
commercial or investigational bortezomib is used) must be reported to Millennium 
Pharmacovigilance (or designee).  See Section 4.2 for the reporting of SAEs. 
The sponsor-investigator is responsible to meet all regulations and requirements applicable to 
the sponsor-investigator. 
 
4.1 Definitions 
 
4.1.1 Adverse Event Definition 
 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether or 
not it is related to the medicinal product.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug. 
 


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For this protocol an abnormal laboratory value will not be assessed as an AE unless that value 
leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or 
is considered by the investigator to be a clinically significant change from baseline. 
 
4.1.2  Serious Adverse Event Definition 
Serious adverse event (SAE) means any untoward medical occurrence that at any dose: 
 Results in death. 
 Is life-threatening.  (refers to an AE in which the patient was at risk of death at 
the time of the event.  It does not refer to an event which hypothetically might 
have caused death if it were more severe). 
 Requires inpatient hospitalization or prolongation of existing hospitalization.  
(see clarification below on planned hospitalizations in Section Error! Reference 
source not found.). 
 Results in persistent or significant disability/incapacity.  Disability is defined 
as a substantial disruption of a persons’ ability to conduct normal life functions. 
 Is a congenital anomaly/birth defect. 
 Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the 
patient, require medical or surgical intervention to prevent 1 of the outcomes 
listed above, or involves suspected transmission via a medicinal product of an 
infectious agent.   Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse; any organism, virus, or 
infectious particle (eg, prion protein transmitting Transmissible Spongiform 
Encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent. 
Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous.  The general term severe is often used to describe the intensity (severity) of a 
specific event; the event itself, however, may be of relatively minor medical significance 
(such as a Grade 3 headache).  This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function.  A severe AE (Grade 3 or 4) 
does not necessarily need to be considered serious.  For example, a white blood cell count of 
1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered 
serious.  Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations. 
 
4.2 Procedures for AE and SAE Reporting 
 
AEs may be spontaneously reported by the patient and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other diagnostic 
procedures.  Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE.  When possible, signs and symptoms indicating a common 


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underlying pathology should be noted as one comprehensive event.  AEs which are serious 
must be reported to Millennium Pharmacovigilance (or designee) from the first dose of 
bortezomib up to and including 30 days after administration of the last dost of bortezomib. 
Any SAE that occurs at any time after completion of bortezomib treatment or after the 
designated follow-up period that the sponsor-investigator and/or sub-investigator considers to 
be related to any study drug must be reported to Millennium Pharmacovigilance (or 
designee).  Planned hospital admissions or surgical procedures for an illness or disease that 
existed before the patient was enrolled in the trial are not to be considered AEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was performed 
earlier or later than planned).  All SAEs should be monitored until they are resolved or are 
clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es). 
Since this is an investigator-initiated study, the principal investigator 
, also 
referred to as the sponsor-investigator, is responsible for reporting serious adverse events 
(SAEs) to any regulatory agency and to the sponsor- investigator’s EC or IRB.   Regardless 
of expectedness or causality, all SAEs (including serious pretreatment events) must also be 
reported to Millennium Pharmacovigilance. 
Fatal and Life Threatening SAEs within 24 hours but no later than 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event 
 
All other serious (non-fatal/non life threatening) events within 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event 
 
The protocol may include language to specify expected adverse events which will not be 
considered serious and will not require expedited reporting. 
 
See below for contact information for the reporting of SAEs to Millennium 
Pharmacovigilance.   
The sponsor-investigator must fax the SAE Form per the timelines above.  A sample of an 
SAE Form will be provided.   
The SAE report must include at minimum: 
 Event term(s) 
 Serious criteria 
 Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will be 
determined by using the NCI CTCAE version specified in the protocol, as a 
guideline, whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
 Causality of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration.  


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Follow-up information on the SAE may be requested by Millennium.    
Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI 
CTCAE version used at your institution, as a guideline, whenever possible.  The criteria are 
available online at http://ctep.cancer.gov/reporting/ctc.html. 
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure that 
the SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites 
participating in the study.  Sub-investigators must report all SAEs to the sponsor-investigator 
so that the sponsor-investigator can meet his/her foregoing reporting obligations to the 
required regulatory agencies and to Millennium Pharmacovigilance, unless otherwise agreed 
between the sponsor-investigator and sub-investigator(s).   
Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study products as soon 
as possible but no later than 4 calendar days of such communication. 
SAE and 
 
 
 
 
 
 
 
 
 
Suggested Reporting Form: 
 SAE Report Form (a sample is provided in Appendix Error! Reference source not 
found.) 
 US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 Any other form deemed appropriate by the sponsor-investigator 
 
4.3 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study drug.  
The sponsor-investigator must fax a completed Pregnancy Form to the Millennium 
Department of Pharmacovigilance or designee (see Section 4.2).  The pregnancy must be 
followed for the final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s participation 
in this study, the sponsor-investigator must also immediately fax a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 4.2).  
Every effort should be made to follow the pregnancy for the final pregnancy outcome. 
Suggested Pregnancy Reporting Form: Pregnancy Report Form (Appendix 8.15) 


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5 STATISTICAL PROCEDURES 
 
5.1 Sample Size Estimation 
 
The sample size calculation for this one-arm trial is based on an endpoint of 18-month 
survival rate with a 36-month accrual period (1-2 patients/month).  The following 
assumptions are made:  1. Survival time follows an exponential distribution, 2. The 
18-month survival rate is 55% (median survival 21 months) for the new treatment and 
40% (median survival 14 months) for the standard treatment (based on (Stupp, Mason 
et al. 2005), 3. The 18-month survival rate is estimated using the Kaplan-Meier 
method, 4. Test statistics – Z-test, Type I error=0.05, 5. N=50 (total patients).  In a 
performed simulation, the power is 70% for 1-sided test. 
 
5.2 Randomization and Stratification 
Not applicable 
 
5.3 Populations for Analysis 
This study will be a multi-center, open-label, phase II study assessing safety and 
efficacy in adult newly-diagnosed GBM patients that have had no prior therapy other 
than surgery.  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. 
 
5.4 Procedures for Handling Missing, Unused, and Spurious Data 
All data will be stored in the patient’s medical record and duplicates or research specific 
CRFs in their research records.  We will only be collecting data that is relevant for this 
study.  All unused data will be stored per medical records policy and procedures for 
handling of medical records. 
 
5.5 Statistical Methods 
 
5.5.1 Baseline Comparisons 
 
The primary endpoint will be total survival from the date of surgical-pathological diagnosis.  
For the final analysis, results will be compared with the results on comparable patients whose 
data are available through the UCLA Neuro-oncology Department database.  These 
comparable patients were all newly diagnosed GBM patients who were treated on research 
protocols and similar to the patients in the present study insofar as they will be patients seen 
at a tertiary center and enrolled into clinical trials early after diagnosis.  The primary analysis 
will utilize a Cox proportional hazards model including age, KPS, and extent of resection.  
This allows for adjustment for major prognostic factors. 
 
5.5.2 Efficacy Analysis 
 
Primary Efficacy Variables 
Overall Survival 


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Secondary Efficacy Variables 
12-month survival and median time to tumor progression tumor response as assessed 
by MRI and neurologic exam, toxicity. 
 
The patients will have a brain MRI evaluation of response and progression every 8 
weeks, starting from the day 56 scan obtained 2 weeks after completion of radiation 
and daily temozolomide.  Assessment will be conducted on a 7-point scale.  This scale 
is expected to be more useful in this study because many newly-diagnosed patients 
are likely not to have evaluable disease due to gross total resections.  A -2 or -3 
assessment will be taken as progression.  Determination of whether progression 
occurs based on the day 56 scan will take into account the untreated window between 
baseline MRI and day of 1 of the study. 
 
complete resolution of tumor: 3 
tumor definitely smaller: 2  
tumor probably smaller: 1  
tumor unchanged: 0  
tumor probably worse: -1  
tumor definitely worse: -2  
new lesion: -3 
 
Neurological Exam: Although not used for determining response, it is useful to evaluate 
improvement in the neurologic exam that should coincide with objective measurement of 
tumor size. 
 
+2 
Definitely better 
+1 
Possibly better 
  0 
Unchanged 
 -1 
Possibly worse 
 -2 
Definitely worse 
  B 
Baseline 
 
Performance Status, Neurological Function, and Mental Status: Patients will be 
graded according to Karnofsky Performance Status, Neurological Function 
and Mental Status (see Appendix 8.2). 
 
Time to Treatment Failure: From date of registration to the date of first observation of 
progressive disease, non-reversible neurologic progression or permanently 
increased steroid requirement (applies to stable disease only), death due to any 
cause, or early discontinuation of treatment. 
 
Time to Death: From date of registration to date of death due to any cause. 
 
Molecular Analysis: Pre-treatment biomarker data (MGMT and IDH1) and additional 
correlative markers will be analyzed and descriptive statistics will be generated.  
Exploratory analyses of a graphical nature comparing the biomarker data with the best 
overall response (CR, PR, SD, PD) are also planned. 
 


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5.5.3 Safety Analysis 
The PI will be responsible for accurate, consistent, timely, complete, and reliable data 
collection. 
 
The study coordinator and PI are responsible for ensuring that the following forms are 
completed in a legible and timely manner for every patient enrolled on study. These 
forms are an integral part of the study data and will be maintained in the patient’s 
clinical chart at UCLA.  Errors on the forms should be lined through, but not 
obliterated with the correction inserted, initialed and dated by the study coordinator or 
PI. These forms will be available at all times for inspection by the FDA and UCLA.  
 
Registration Form  
On-study Eligibility Checklist 
UCLA Adverse Event Form 
MedWatch Form (Form 3500) 
 
In addition to the patient data maintained on the forms listed above, patient data will 
also be entered into a Microsoft Excel spreadsheet or database. The data are backed 
up daily and stored on a secure medical center server. The PI, study investigators and 
data coordinator for the study are the only individuals who will have access to the 
password-protected data file. 
 
Quality assurance measures are provided by three mechanisms: 1) ongoing 
monitoring of protocol compliance, 2) on-site audits, and 3) response reviews. 
Monitoring will begin at the time of patient registration and will continue during 
protocol performance and completion. This trial is subject to Cancer Center Internal 
Quality Assurance Monitoring. 
 
Data and the progress of this trial will be reported to the DSMB at regular intervals as 
determined by the DSMB.  The first data summary report will be due quarterly, 
starting from the date of the IRB approval. 
 
JCCC DSMB 
This trial is subject to the Jonsson Comprehensive Cancer Center Internal Quality Assurance 
program. 
 
The JCCC Data and Safety Monitoring Board (DSMB) meets monthly to review all serious 
adverse event reports for trials overseen by the JCCC DSMB.  All serious adverse event 
(SAE) reports, which have been filed since the previous meeting, are presented to the 
committee for review. 
 
For all trials where the JCCC DSMB has primary oversight for SAE review, all SAEs 
occurring within these studies shall be reported to the JCCC DSMB in a timely manner 
consistent with the UCLA IRB time requirements [ten days, two days for a death] regardless 
of relationship, expectedness or severity.  The JCCC Office of Regulatory Compliance 
(ORC) will review all submissions and the ORC staff will enter the information into the 
JCCC Clinical Trials database.  Reports are generated for full JCCC DSMB review of those 
SAEs that have some component of relatedness to the study drug and may, at the discretion 
of the JCCC compliance officers, include SAE reports that may require DSMB review.  For 
trials where the JCCC DSMB has primary DSMB review responsibility, the DSMB will 


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request that the PI generate cumulative adverse event reports for quarterly, biannual or annual 
review.  
 
The DSMB reviews each SAE report and determines whether or not protocol modifications 
are warranted to ensure subject safety.  In this review, prior occurrences of similar toxicity 
with the therapy under study are taken into consideration, as well as the servity of the event 
and the likelihood that it was related to a study drug.  The DSMB may recommend no 
changes to the study if the event is expected or related to other causes such as the subject’s 
underlying condition.  The DSMB may request an expert’s advice of another non-Principal 
Investigator with national experience to support their deliberations and decisions.  The JCCC 
DSMB has the authority to recommend to the UCLA IRB the immediate halt to the study 
(i.e., discontinuation of any further treatment of enrolled subjects and discontinuation of 
enrollment of new subjects) should there be any serious unexpected toxicity that warrants 
further investigation.  JCCC DSMB correspondences are addressed to the Principal 
Investigator and copied to the UCLA IRB.  Minutes of the DSMB meetings are recorded and 
processed into the computer file. 
 
Monitoring, Auditing and Reporting  
The NIH and NCI policy statements allow for variable monitoring and reporting plans, 
commensurate with the potential risks and with the size and complexity of the trial.  The 
monitoring plan must be sufficiently rigorous and effective to ensure subject safely and to 
ensure protocol compliance and data validity and integrity.  
 
Level of Risk of a Study 
All interventional clinical trials undergo scientific review by the Internal Scientific Peer 
Review Committee (ISPRC) which requires that a Data and Safety Monitoring Plan is in 
place before a trial can be approved to begin.  For trials overseen by the JCCC DSMB, the 
JCCC DSMB will determine the degree of risk of the study and will ensure that there are 
procedures in place to ensure the safety of the subjects that are enrolled in the trial.  The 
intensity level of the monitoring is determined by the risk category.  Some of the factors that 
must be considered when assigning the Level of Risk category include: 
 
1. A biostatistical design and appropriate procedures for proper data management so that 
the information collected can be properly validated. 
2. Appropriate Serious Adverse Event reporting procedures must be in place. 
3. The study duration must be appropriate and must be based on a realistic rate of 
enrollment. 
4. Data collection and data management must be adequate to verify and ensure subject 
eligibility. 
 
Assignment of risk 
 
Assigning risk ensures that the data and safety monitoring is based on the level of risk (low, 
medium, or high) to ensure that the data and safety monitoring activities are appropriate.  
Below are some of the criteria used to make a decision regarding the assignment of risk: 
 Expected duration of the study based upon the estimated rate of enrollment. 
 Type of study population (e.g., children, geriatric) 
 The procedures used in the trial are commensurate with the degree of risk. 
 Adequate data management systems in place and appropriate case report forms 


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 Proper serious adverse event reporting procedures in place 
 Proper biostatistical design and data analysis procedures in place. 
 
Level of Risk 
 
Level 2  
 
Example of type of trial: 
Institutional study for which IND is exempt by FDA.  Examples are studies using 
commercially available agents for an unapproved indication based on standard regimen.  
1. Compliance Officer meets with PI/Staff prior to study initiation; review regulatory 
requirements and operating system.  Compliance Officer provides real time 
monitoring to determine eligibility prior to enrollment onto the protocol. 
2. Real time QA monitoring of the subjects and data collection occurs for all subjects 
entered onto the trial.  
3. Comprehensive QA auditing within first year or first 10 subjects enrolled, whichever 
comes first.  Subsequent audit frequency will be annually.  
4. Frequency of DSMB Summary Report is typically on a biannual basis or 
approximately every six months. 
 
Monitoring and Auditing Activities 
 
The compliance officer of the JCCC Office of Regulatory Compliance [ORC] will monitor 
the clinical records for all human subjects enrolled onto JCCC trials overseen by the JCCC 
DSMB.  The JCCC compliance officer will perform real time review of informed consent 
processes and the meeting of all inclusion and exclusion criteria and screening results at study 
entry.  Active monitoring will offer the JCCC study teams prospective information that can 
be used to enhance the quality of research being performed contemporaneously.  Auditing is 
a review of historic performance of the research effort and is performed on case report forms, 
regulatory files and source documents to measure the quality of the research effort in a 
retrospective manner.    
 
This study will be conducted at UCLA Medical Center and Columbia University Medical 
Center. The study will be monitored by the UCLA JCCC Quality Assurance Program and 
they may perform audits of the Columbia University Medical Center if deemed necessary. In 
addition, a monthly team conference will be done among study investigators from all external 
network study sites during which toxicity data including all SAEs will be reviewed and other 
issues relevant to the study such as interim assessment of accrual, outcome and compliance 
with study guidelines. 
 
The PI will be responsible for ensuring that study monitoring requirements are met. Upon 
request the monthly safety meeting agenda will be submitted also to the UCLA JCCC Quality 
Assurance Program. The quality control procedure of data and protocol adherence will be 
performed through a site visit and/or teleconference at external network study sites by the 
study coordination center personnel from the UCLA Neuro-Oncology Center at least once a 
year.  Copies of all monitoring and audit reports at external study sites will be provided to 
UCLA JCCC DSMB. 
 


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5.5.4  For this multi-center clinical trial, the following organizations are involved in the 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All clinical sites are responsible for the recruitment, treatment, and evaluation of patients 
with newly diagnosed brain tumor who meet eligibility criteria.  Each site will include one or 
more responsible physicians/ investigators, and a study coordinator.  The investigator and 
coordinator from the study coordination center, UCLA Neuro-Oncology Program, who 
represents the institution, will provide oversight of the following procedures at external 
network study sites including eligibility verification. 
 
– Eligibility Screening: FAX a copy of the eligibility checklist form and registration 
form to 
 review and 
verification of eligibility.  No exemption will be granted for any study entry at 
external network sites without prior approval by the PI.  
 
– Clinical evaluation: all data will be captured and recorded on the case report forms 
provided.  The quality control procedure of data and protocol adherence will be 
performed through a site visit to each network site by study coordination center 
personnel from UCLA Neuro-Oncology Center. Study oversight will begin at the time 
of subject registration and will continue during protocol performance and completion.  
Monthly safety meeting will take place in order to review of currently enrolled 
patients at each site. 
 
– Data Management: updating and maintenance of case report forms and subjects files, 
solving the data queries, updating and maintenance of subject’s status log, reporting 
all SAEs occurring at sites. 
 
a) The above referenced study will have an externally constituted safety 
monitoring group.  In addition, external sites have their own DSMB plans.  
 
b)  Safety data is reviewed on a continual basis as adverse events and reports 
of toxicities, laboratory findings and reports of Serious Adverse Events are 
received.   
 
c) Serious adverse events are reported to the main coordination center using 




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6 ADMINISTRATIVE REQUIREMENTS 
 
6.1 Product Complaints 
 
A product complaint is a verbal, written, or electronic expression which implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug product.  
Individuals who identify a potential product complaint situation should immediately contact 
MedComm Solutions (see the following) and report the event.  Whenever possible, the 
associated product should be maintained in accordance with the label instructions pending 
further guidance from a Millennium quality representative. 
 
A medication error is a preventable event that involves an identifiable patient and that leads 
to inappropriate medication use, which may result in patient harm.  While overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not.  
Individuals who identify a potential medication error situation should immediately contact 
MedComm Solutions (see below) and report the event. 
 
  
 
 
 
 
Product complaints and medication errors in and of themselves are not AEs.  If a 
product complaint or medication error results in an SAE, an SAE form should be 
completed and sent to PPD (refer to Section 4.2). 
 


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7 REFERENCES 
Amiri, K. I., L. W. Horton, et al. (2004). "Augmenting Chemosensitivity of Malignant Melanoma 
Tumors via Proteasome Inhibition: Implication for Bortezomib (VELCADE, PS-341) as a 
Therapeutic Agent for Malignant Melanoma." Cancer Res %R 10.1158/0008-5472.CAN-04-
067364(14): 4912-4918. 
Berges, O., D. Decaudin, et al. (2008). "Concurrent radiation therapy and bortezomib in myeloma 
patient." Radiother Oncol86(2): 290-2. 
Bredel, M., C. Bredel, et al. (2006). "Tumor necrosis factor-alpha-induced protein 3 as a putative 
regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human 
glioblastomas."J Clin Oncol24(2): 274-87. 
Bredel M, Scholtens DM, Yadav AK, et al. NFKBIA Deletion in Glioblastomas. New Engl J 
Med.2011;364(7):627-637. 
Butowski, N., M. D. Prados, et al. (2005). "A phase II study of concurrent temozolomide and cis-
retinoic acid with radiation for adult patients with newly diagnosed supratentorial 
glioblastoma."Int J Radiat Oncol Biol Phys61(5): 1454-9. 
Davies, A. M., P. N. Lara, Jr., et al. (2007). "Incorporating Bortezomib into the Treatment of Lung 
Cancer." Clin Cancer Res %R 10.1158/1078-0432.CCR-07-033413(15): 4647s-4651. 
Edelman, M. J. (2005). "The potential role of bortezomib in combination with chemotherapy and 
radiation in non-small-cell lung cancer." Clin Lung Cancer7 Suppl 2: S64-6. 
Kubicek, G. J., M. Werner-Wasik, et al. (2008). "Phase I Trial Using Proteasome Inhibitor 
Bortezomib and Concurrent Temozolomide and Radiotherapy for Central Nervous System 
Malignancies." Int J Radiat Oncol Biol Phys. 
Lai, A., E. Filka, et al. (2008). "Phase II Pilot Study of Bevacizumab in Combination With 
Temozolomide and Regional Radiation Therapy for Up-Front Treatment of Patients With 
Newly Diagnosed Glioblastoma Multiforme: Interim Analysis of Safety and Tolerability." Int 
J Radiat Oncol Biol Phys. 
Orlowski, R. Z. and D. J. Kuhn (2008). "Proteasome Inhibitors in Cancer Therapy: Lessons from the 
First Decade." Clin Cancer Res %R 10.1158/1078-0432.CCR-07-221814(6): 1649-1657. 
Raychaudhuri, B., Y. Han, et al. (2007). "Aberrant constitutive activation of nuclear factor kappaB in 
glioblastoma multiforme drives invasive phenotype." J Neurooncol85(1): 39-47. 
Robins, H. I., M. Won, et al. (2006). "Phase 2 trial of radiation plus high-dose tamoxifen for 
glioblastoma multiforme: RTOG protocol BR-0021 
10.1215/S1522851705000311." Neuro-oncol8(1): 47-52. 
Russo, S. M., J. E. Tepper, et al. (2001). "Enhancement of radiosensitivity by proteasome inhibition: 
implications for a role of NF-kappaB." Int J Radiat Oncol Biol Phys50(1): 183-93. 
Stupp, R., W. P. Mason, et al. (2005). "Radiotherapy plus concomitant and adjuvant temozolomide for 
glioblastoma." N Engl J Med352(10): 987-96. 
Styczynski, J., D. Olszewska-Slonina, et al. (2006). "Activity of bortezomib in glioblastoma." 
Anticancer Res26(6B): 4499-503. 
Van Waes, C., A. A. Chang, et al. (2005). "Inhibition of nuclear factor-kappaB and target genes 
during combined therapy with proteasome inhibitor bortezomib and reirradiation in patients 
with recurrent head-and-neck squamous cell carcinoma." Int J Radiat Oncol Biol Phys63(5): 
1400-12. 
Wrensch, M., Y. Minn, et al. (2002). "Epidemiology of primary brain tumors: current concepts and 
review of the literature." Neuro-oncol4(4): 278-99. 
Yamini, B., X. Yu, et al. (2007). "Inhibition of nuclear factor-kappaB activity by temozolomide 
involves O6-methylguanine induced inhibition of p65 DNA binding." Cancer Res67(14): 
6889-98. 


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Yin, D., H. Zhou, et al. (2005). "Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis 
in human glioblastoma multiforme (GBM)." Oncogene24(3): 344-54. 


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 VELCADE REFERENCES 
Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD et al. Proteasome 
inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999; 59 
(11):2615-22. 
Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al. Criteria for 
evaluating disease response and progression in patients with multiple myeloma treated by 
high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of 
the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102 
(5):1115-23. 
Cusack JC, Jr., Liu R, Houston M, Abendroth K, Elliott PJ, Adams J et al. Enhanced 
chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic 
nuclear factor-kappaB inhibition. Cancer Res 2001; 61 (9):3535-40. 
Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F et al. Randomized phase 
III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-
small-cell lung cancer previously treated with platinum-containing chemotherapy 
regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000; 
18 (12):2354-62. 
Fossella F. Docetaxel + Cisplatin (DC) and Docetaxel + Carboplatin (DCb) vs Vinorelbine + 
Cisplatin (VC) in chemotherapy-naïve patients with advanced and metastatic non-small 
cell lung cancer (NSCLC): Results of a multicenter, randomized phase III study. 
European Journal of Cancer, European Cancer Conference, ECCO 11, 2001; Lisbon, 
Portugal. 37(suppl 6):S154. Abstract 562  
Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J et al. The 
proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug 
resistance in human multiple myeloma cells. Cancer Res 2001; 61 (7):3071-6. 
Jagannath S, Barlogie B, Berenson J et al. A Phase 2 study of two doses of bortezomib in 
relapsed or refractory myeloma. Br J Haematol 2004: 127:165-172 
LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N et al. 
Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs 
survival in a murine model. Cancer Res 2002; 62 (17):4996-5000. 
Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ. Proteasome inhibition 
measurements: clinical application. Clin Chem 2000; 46 (5):673-83. 
McConkey DJ, Pettaway C, Elliott P, Adam J, Papandreou C, Herrmann JL et al. The 
proteasome as a new drug target in metastatic prostate cancer. 7th Annual Genitourinary 
Oncology Conference, 1999; Houston, TX. Abstract  
Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S et al. Phase I 
Trial of the Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic 
Malignancies. J Clin Oncol 2002; 20 (22):4420-7. 
Papandreou C, Daliani D, Millikan RE, Tu S, Pagliaro L, Adam J. Phase I Study of 
Intravenous (I.V.) Proteasome Inhibitor PS-341 in Patients (Pts) with Advanced 
Malignancies. Proc Am Soc Clin Oncol, 2001. Abstract 340  
Pink MM, Pien CS, Ona VO, Worland P, Adams J, Kauffman MG. PS-341 enhances 
chemotherapeutic effect in human xenograft models. Proc Am Assoc Cancer Res, 2002; 
San Francisco, CA. Abstract 787 


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Richardson PG, Barlogie B, Berenson J et al. A Phase II study of Bortezomib in Relapsed, 
Refractory Myeloma. N Engl J Med 2003; 348:2609-2617 
Richardson PG, et al., Bortezomib or High-Dose Dexamethasone for Relapsed Multiple 
Myeloma. N Engl J Med 2005; 352:2487-98.  
Richardson et al, Bortezomib Continues to Demonstrate Superior Efficacy Compared With 
High-Dose Dexamethasone in Relapsed Multiple Myeloma: Updated Results of the 
APEX Trial. Blood, 2005; 106: Abstract 2547. 
Steiner P, Neumeier H, Lightcap E, Sadis S, Pien C, Pink M et al. Adaptation of Human 
Tumor Cell Lines to PS-341. AACR-NCI-EORTC International Conference, 2001; 
Miami Beach, FL. Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 
02139. Abstract  
Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-341 in 
cancer therapy. Clin Cancer Res 1999; 5 (9):2638-45. 
VELCADE (bortezomib) [package insert]. Cambridge, MA: Millennium Pharmaceuticals, 
Inc.; 2003. 
1 Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, et al. 
Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 
1999;59(11):2615-22. 
2Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-
341 in cancer therapy. Clin Cancer Res 1999;5(9):2638-45. 
3 Cusack JC, Jr., Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, et al. Enhanced 
chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic 
nuclear factor-kappaB inhibition. Cancer Res 2001;61(9):3535-40. 
4 LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, et al. 
Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs 
survival in a murine model. Cancer Res 2002;62(17):4996-5000. 
5 Williams S, Pettaway C, Song R, Papandreou C, Logothetis C, McConkey DJ. 
Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis 
in human prostate tumor xenografts. Mol Cancer Ther 2003;2(9):835-43. 
6 Nawrocki ST, Bruns CJ, Harbison MT, Bold RJ, Gotsch BS, Abbruzzese JL, et al. 
Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic 
human pancreatic tumor xenografts. Mol Cancer Ther 2002;1(14):1243-53. 
7 Satou Y, Nosaka K, Koya Y, Yasunaga JI, Toyokuni S, Matsuoka M. Proteasome 
inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in 
vivo and in vitro. Leukemia 2004;18:1357-63. 
8 Boccadoro M, Morgan G, Cavenagh J. Preclinical evaluation of the proteasome 
inhibitor bortezomib in cancer therapy. Cancer Cell Int 2005;5:18. 
 
 
9 Goel A, Dispenzieri A, Geyer SM, Greiner S, Peng KW, Russell SJ. Synergistic activity 
of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletally 
targeted radiotherapy in an orthotopic model of multiple myeloma. Blood 
2006;107(10):4063-70. 
10 Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, et al. The 
proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to 
conventional chemotherapeutic agents: therapeutic applications. Blood 
2003;101(6):2377-80. 


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11 Sayers TJ, Brooks AD, Koh CY, Ma W, Seki N, Raziuddin A, et al. The proteasome 
inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing 
levels of c-FLIP. Blood 2003;102(1):303-10. 
12 Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasome inhibitor 
bortezomib interacts synergistically with histone deacetylase inhibitors to induce 
apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood 2003;102(10):3765-
74. 
13 O'Connor OA, Smith EA, Toner LE, Teruya-Feldstein J, Frankel S, Rolfe M, et al. The 
combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule 
oblimersen sensitizes human B-cell lymphomas to cyclophosphamide. Clin Cancer Res. 
2006;12(9):2902-11. 
14 David E, Sun SY, Waller EK, Chen J, Khuri FR, Lonial S. The combination of the 
farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces 
synergistic apoptosis in human myeloma cells that is associated with down-regulation of 
p-AKT. Blood 2005;106(13):4322-9. 
15 McConkey DJ, Pettaway C, Elliott P, Adam J, Papandreou C, Herrmann JL, et al. The 
proteasome as a new drug target in metastatic prostate cancer. In: 7th Annual 
Genitourinary Oncology Conference; 1999 February 1999; Houston, TX. 
16 Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, et al. The 
proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug 
resistance in human multiple myeloma cells. Cancer Res 2001;61(7):3071-6. 
17 Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH. 
Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma 
cells. Blood 2006;107(12):4907-16. 
18 Ling YH, Liebes L, Ng B, Buckley M, Elliott PJ, Adams J, et al. PS-341, a novel 
proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-
M phase 
19 Yang Y, Ikezoe T, Saito T, Kobayashi M, Koeffler HP, Taguchi H. Proteasome 
inhibitor PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells 
via the JNK/c-Jun/AP-1 signaling. Cancer Sci 2004;95(2):176-80. 
20 Kaluz S, Kaluzova M, Stanbridge EJ. Proteasomal inhibition attenuates transcriptional 
activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-
terminal activation domain. Mol Cell Biol 2006;26(15):5895-907. 
21 An WG, Hwang SG, Trepel JB, Blagosklonny MV. Protease inhibitor-induced 
apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are 
independent markers of proteasome inhibition. Leukemia 2000;14(7):1276-83. 
22 Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, et al. Bortezomib 
mediates antiangiogenesis in multiple myeloma via direct and indirect effects on 
endothelial cells. Cancer Res 2006;66(1):184-91. 
23 Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, et al. 
Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl 
Acad Sci U S A 2002;99(22):14374-9. 
24 Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ. Proteasome 
inhibition measurements: clinical application. Clin Chem 2000;46(5):673-83. 
25 Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. 
Phase I Trial of the Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic 
Malignancies. J Clin Oncol 2002;20(22):4420-7. 


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26 Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. 
Phase I Trial of the Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic 
Malignancies. J Clin Oncol 2002;20(22):4420-7. 
27 Aghajanian C, Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ, et al. A Phase I Trial 
of the Novel Proteasome Inhibitor PS341 in Advanced Solid Tumor Malignancies. Clin 
Cancer Res 2002;8(8):2505-11. 
28 Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, et al. Phase I trial of 
the proteasome inhibitor bortezomib in patients with advanced solid tumors with 
observations in androgen-independent prostate cancer. J Clin Oncol 2004;22(11):2108-
21. 
291 Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Castritis E, Bitsaktsis A, 
Pangalis GA. Treatment of relapsed or refractory Waldenström's macroglobulinemia with 
bortezomib. Haematologic. 2005;90(12):1655-8. 
30 Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, et al. A phase 
2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 
2004;127(2):165-72. 
31 Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A Phase 
2 Study of Bortezomib in Relapsed, Refractory Myeloma. N Engl J Med 
2003;348(26):2609-17. 
32 Bladé J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, et al. Criteria for 
evaluating disease response and progression in patients with multiple myeloma treated by 
high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of 
the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 
1998;102(5):1115-23. 
33 Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. 
Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma. N Engl J 
Med 2005;352(24):2487-98. 
34 Richardson P, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, et al. 
Bortezomib Continues Demonstrates Superior Efficacy Compared with High-Dose 
Dexamethasone in Relapsed Multiple Myeloma: Updated Results of the APEX Trail. 
Blood 2005;106(11):Abstract 2547. 
35 Fisher R, Bernstein S, Kahl B, Djulbegovic B, Robertson M, de Vos S, et al. 
Multicenter Phase II Study of Bortezomib in Patients With Relapsed or Refractory Mantle 
Cell Lymphoma. J Clin Oncol 2006;24(30):4867-74. 
36Goy A, Bernstein S, Kahl B, Djulbegovic B, Robertson M, Vos S, et al. Durable 
Responses with Bortezomib in Patients with Relapsed or Refractory mantle Cell 
Lymphoma:  Updated Time-to-Event Analyses of the Multicenter PINNACLE Study. 
Blood 2007;110:Abstract 125. 
37 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et 
al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. 
N Engl J Med 2008;359(9):906-17. 
38 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et 
al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. 
N Engl J Med 2008;359(9):906-17. 
 




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8.2 
 Karnofsky Performance Status Scale (The following table presents the 
Karnofsky performance status scale1 ) 
Points 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or to do active work 
60 
Requires occasional assistance but is able to care for most of his/her needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization indicated.  Death not imminent 
20 
Very sick; hospitalization necessary; active support treatment necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
 
 
NEUROLOGICAL FUNCTION – CIRCLE ONE 
 
 
DESCRIPTION 
 
 
0 
No neurologic symptoms; fully active at home/work without assistance 
1 
Minor neurologic symptoms; fully active at home/work without assistance 
2 
Moderate neurologic symptoms; fully active at home/work but requires assistance 
3 
Moderate neurologic symptoms; less than fully active at home/work and requires 
assistance 
4 
Severe neurologic symptoms; totally inactive requiring complete assistance at home 
or institution; unable to work 
 
 
 
MENTAL STATUS – CIRCLE ONE 
 
 
DESCRIPTION 
 
 
0 
Normal function 
1 
Minor mental confusion 
2 
Gross confusion but awake 
9 
Unknown 
 
 
 
                                                 
1 
Mor V, Laliberte L, Morris JN, Wiemann M.  The Karnofsky Performance Status Scale:  
an examination of its reliability and validity in a research setting.  Cancer 1984; 53:2002-
2007. 


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8.3 
Body Surface Area and Creatinine Clearance Calculations 
Body surface area (BSA) should be calculated using the DuBois (preferable) or the Mosteller 
formula.  
 
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as follows: 
 
CrCl (ml/min) =  (140-age) (actual wt in kg)              
 
 
 
   72 x serum creatinine (mg/dl) 
For females use 85% of calculated CrCl value. 
Note: In markedly obese patients, the Cockroft-Gault formula will tend to overestimate the 
creatinine clearance. (Adipose tissue tends to contribute little creatinine requiring renal 
clearance.) 
 


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8.4 
New York Heart Association Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease: 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_______________________________ 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, 
Brown & Co; 1994:253-256. 


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8.5 
Declaration of Helsinki 
World Medical Association Declaration of Helsinki: 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by 
the 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General 
Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, 
September 1989 48th WMA General Assembly, Somerset West, Republic of South Africa, 
October 1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
 
A. INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other participants in medical 
research involving human subjects.  Medical research involving human subjects includes 
research on identifiable human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people.  The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the patient's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the patient." 
4. Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
5. In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the 
aetiology and pathogenesis of disease.  Even the best proven prophylactic, diagnostic, and 
therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human beings 
and protect their health and rights.  Some research populations are vulnerable and need 
special protection.  The particular needs of the economically and medically disadvantaged 
must be recognized.  Special attention is also required for those who cannot give or refuse 
consent for themselves, for those who may be subject to giving consent under duress, for 
those who will not benefit personally from the research and for those for whom the 
research is combined with care. 
9. Research Investigators should be aware of the ethical, legal and regulatory requirements 
for research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration. 
 


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B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
1. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
2. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation. 
3. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
4. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol.  This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
investigator, the sponsor or any other kind of undue influence.  This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed.  The committee has the right to monitor ongoing 
trials.  The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events.  The researcher should also submit to 
the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
5. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration. 
6. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  
The responsibility for the human subject must always rest with a medically qualified 
person and never rest on the subject of the research, even though the subject has given 
consent. 
7. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to 
the subject or to others.  This does not preclude the participation of healthy volunteers in 
medical research.  The design of all studies should be publicly available. 
8. Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed.  Physicians should cease any investigation if the risks are found to 
outweigh the potential benefits or if there is conclusive proof of positive and beneficial 
results. 
9. Medical research involving human subjects should only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the subject.  This is especially 
important when the human subjects are healthy volunteers. 
10. Medical research is only justified if there is a reasonable likelihood that the populations in 
which the research is carried out stand to benefit from the results of the research. 
11. The subjects must be volunteers and informed participants in the research project. 
12. The right of research subjects to safeguard their integrity must always be respected.  
Every precaution should be taken to respect the privacy of the subject, the confidentiality 


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of the patient's information and to minimize the impact of the study on the subject's 
physical and mental integrity and on the personality of the subject. 
13. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail.  The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal.  After ensuring that the subject has understood the information, the physician 
should then obtain the subject's freely-given informed consent, preferably in writing.  If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
14. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or 
may consent under duress.  In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
15. For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law.  
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent 
to decisions about participation in research, the investigator must obtain that assent in 
addition to the consent of the legally authorized representative. 
17. Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population.  The 
specific reasons for involving research subjects with a condition that renders them unable 
to give informed consent should be stated in the experimental protocol for consideration 
and approval of the review committee.  The protocol should state that consent to remain 
in the research should be obtained as soon as possible from the individual or a legally 
authorized surrogate. 
18. Both authors and publishers have ethical obligations.  In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results.  Negative as 
well as positive results should be published or otherwise publicly available.  Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared 
in the publication.  Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
1. The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value.  
When medical research is combined with medical care, additional standards apply to 
protect the patients who are research subjects. 
2. The benefits, risks, burdens and effectiveness of a new method should be tested against 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 77 of 86 Amendment 7 version dated February 11, 2014 
 
those of the best current prophylactic, diagnostic, and therapeutic methods.  This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists. 
3. At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by 
the study. 
4. The physician should fully inform the patient which aspects of the care are related to the 
research.  The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship. 
5. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic 
measures, if in the physician's judgement it offers hope of saving life, re-establishing 
health or alleviating suffering.  Where possible, these measures should be made the object 
of research, designed to evaluate their safety and efficacy.  In all cases, new information 
should be recorded and, where appropriate, published.  The other relevant guidelines of 
this Declaration should be followed. 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 78 of 86 Amendment 7 version dated February 11, 2014 
 
8.6 
Common Terminology Criteria for Adverse Events Version 3.0 
http://ctep.cancer.gov/reporting/ctc.html  
 
8.7 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme 
Use for toxicity occurring greater than 90 days after radiation therapy. 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Bladder- 
Late RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Slight epithelial 
atrophy/minor 
telangiectasia 
(microscopic 
hematuria) 
Moderate 
frequency / 
generalized 
telangiectasia / 
intermittent 
macroscopic 
hematuria 
Severe frequency 
and 
dysuria/severe 
generalized 
telangiectasia 
(often with 
petechiae); 
frequent 
hematuria; 
reduction in 
bladder capacity 
(<150 cc) 
Necrosis/c
ontracted 
bladder 
(capacity 
<100 cc) / 
severe 
hemorrha
gic cystitis 
Bone- Late 
RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Asymptomatic; 
no growth 
retardation; 
reduced bone 
density 
Moderate pain or 
tenderness; growth 
retardation; 
irregular bone 
sclerosis 
Severe pain or 
tenderness; 
complete arrest 
of bone growth; 
dense bone 
sclerosis 
Necrosis/ 
spontaneo
us fracture 
Brain- Late 
RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Mild headache; 
slight lethargy 
Moderate 
headache; great 
lethargy 
Severe 
headaches; 
severe CNS 
dysfunction 
(partial loss of 
power or 
dyskinesia) 
Seizures 
or 
paralysis; 
coma 
Esophagus
- 
Late RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Mild fibrosis; 
slight difficulty in 
swallowing 
solids; no pain on 
swallowing 
Unable to take solid 
food normally; 
swallowing semi-
solid food; dilatation 
may be indicated 
Severe fibrosis; 
able to swallow 
only liquids; may 
have pain on 
swallowing; 
dilation required 
Necrosis /  
perforation
; fistula 
Heart- Late 
RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Asymptomatic or 
mild symptoms; 
transient T wave 
inversion and ST 
changes; sinus 
tachycardia >110 
(at rest) 
Moderate angina 
on effort; mild 
pericarditis; normal 
heart size; 
persistent abnormal 
T wave and ST 
changes; low QRS 
Severe angina; 
pericardial 
effusion; 
constrictive 
pericarditis; 
moderate heart 
failure; cardiac 
enlargement; 
EKG 
abnormalities 
Tamponad
e / severe 
heart 
failure/sev
ere 
constrictiv
e 
pericarditi
s 
Joint- Late 
RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Mild joint 
stiffness; slight 
limitation of 
movement 
Moderate stiffness; 
intermittent or 
moderate joint pain; 
moderate limitation 
of movement 
Severe joint 
stiffness; pain 
with severe 
limitation of 
movement 
Necrosis / 
complete 
fixation 
Kidney- 
Late RT 
No change 
from 
Transient 
albuminuria; no 
Persistent 
moderate 
Severe 
albuminuria; 
Malignant 
hypertensi


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 79 of 86 Amendment 7 version dated February 11, 2014 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Morbidity 
Scoring 
baseline 
hypertension; 
mild impairment 
of renal function; 
urea 25-35 mg%; 
creatinine 1.5-
2.0 mg%; 
creatinine 
clearance >75% 
albuminuria (2+); 
mild hypertension; 
no related anemia; 
moderate 
impairment of renal 
function; urea >36–
60 mg%; creatinine 
clearance >50-74% 
severe 
hypertension; 
persistent 
anemia 
(<10 g%); severe 
renal failure; urea 
>60 mg%; 
creatinine >4 
mg%; creatinine 
clearance  
<50% 
on; uremic 
coma / 
urea 
>100% 
Larynx- 
Late RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Hoarseness; 
slight arytenoid 
edema 
Moderate arytenoid 
edema; chondritis 
Severe edema; 
severe chondritis 
Necrosis 
Liver- Late 
RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Mild lassitude; 
nausea; 
dyspepsia; 
slightly abnormal 
liver function 
Moderate 
symptoms; some 
abnormal liver 
function tests; 
serum albumin 
normal 
Disabling hepatic 
insufficiency; liver 
function tests 
grossly 
abnormal; low 
albumin; edema 
or ascites 
Necrosis / 
hepatic 
coma or 
en-
cephalopa
thy 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 80 of 86 Amendment 7 version dated February 11, 2014 
 
Grade 
Toxicity 
0 
1 
2 
3 
4 
Lung- Late 
RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Asymptomatic or 
mild symptoms 
(dry cough); 
slight 
radiographic 
appearances 
Moderate 
symptomatic 
fibrosis or 
pneumonitis 
(severe cough); low 
grade fever; patchy 
radiographic 
appearances 
Severe 
symptomatic 
fibrosis or 
pneumonitis; 
dense 
radiographic 
changes 
Severe 
respiratory 
insufficien
cy / 
continuou
s O2 / 
assisted 
ventilation 
Mucous 
membrane
- Late RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Slight atrophy 
and dryness 
Moderate atrophy 
and telangiectasia; 
little mucus 
Marked atrophy 
with complete 
dryness; severe 
telangiectasia 
Ulceration 
Salivary 
glands- 
Late RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Slight dryness of 
mouth; good 
response on 
stimulation 
Moderate dryness 
of mouth; poor 
response on 
stimulation 
Complete 
dryness of 
mouth; no 
response on 
stimulation 
Fibrosis 
Skin- Late 
RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Slight atrophy; 
pigmentation 
change; some 
hair loss 
Patchy atrophy; 
moderate 
telangiectasia; total 
hair loss 
Marked atrophy; 
gross 
telangiectasia 
Ulceration 
Small/Larg
e intestine- 
Late RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Mild diarrhea; 
mild cramping; 
bowel movement 
5 x daily slight 
rectal discharge 
or bleeding 
Moderate diarrhea 
and colic; bowel 
movement >5 x 
daily; excessive 
rectal mucus or 
intermittent 
bleeding 
Obstruction or 
bleeding, 
requiring surgery 
Necrosis / 
perforation 
fistula 
Spinal 
cord- 
Late RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Mild Lhermitte’s 
syndrome 
Severe Lhermitte’s 
syndrome 
Objective 
neurological 
findings at or 
below cord level 
treatment 
Mono-, 
para-, 
quadripleg
ia 
Subcutane
ous tissue- 
Late RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Slight induration 
(fibrosis) and loss 
of subcutaneous 
fat 
Moderate fibrosis 
but asymptomatic; 
slight field 
contracture; <10% 
linear reduction 
Severe induration 
and loss of 
subcutaneous 
tissue; field 
contracture 
>10% linear 
measurement 
Necrosis 
Eye- Late 
RT 
Morbidity 
Scoring 
No change 
from 
baseline 
Asymptomatic 
cataract; minor 
corneal 
ulceration or 
keratitis 
Symptomatic 
cataract; moderate 
corneal ulceration; 
minor retinopathy 
or glaucoma 
Severe keratitis; 
severe 
retinopathy or 
detachment; 
severe glaucoma 
Panophth
al-mitis; 
blindness 
Radiation-
Other 
(Specify, 
________) 
None 
Mild 
Moderate 
Severe 
Life-
threatenin
g or 
disabling 
 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 81 of 86 Amendment 7 version dated February 11, 2014 
 
8.8 
FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 
FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 
 
By circling one (1) number per line, please indicate how true each statement has been for you 
during the past 7 days. 
 
ADDITIONAL CONCERNS 
Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
I have numbness or tingling in my hands……… 
0 
1 
2 
3 
4 
I have numbness or tingling in my feet………… 
0 
1 
2 
3 
4 
I feel discomfort in my hands…………………. 
0 
1 
2 
3 
4 
I feel discomfort in my feet…………………… 
0 
1 
2 
3 
4 
I have joint pain or muscle cramps…………… 
0 
1 
2 
3 
4 
I feel weak all over…………………………… 
0 
1 
2 
3 
4 
I have trouble hearing………………………… 
0 
1 
2 
3 
4 
I get a ringing or buzzing in my ears………… 
0 
1 
2 
3 
4 
I have trouble buttoning buttons……………… 
0 
1 
2 
3 
4 
I have trouble feeling the shape of small objects 
when they are in my hand……………………… 
0 
1 
2 
3 
4 
I have trouble walking………………………… 
0 
1 
2 
3 
4 
________________________________ 
Sources:  Cella DF, Tulsky DS, Gray G, Sarafian B, Lloyd S, Linn E, et al.  The functional 
assessment of cancer therapy (FACT) scale:  development and validation of the general measure.  J 
Clin Oncol 1993;11(3):570-79. 
 
8.9 
Sample Collection and Handling Requirements; 20S Proteasome Inhibition 
Assay 
Not applicable. 
 
8.10 
Sample Collection and Handling Requirements; PK 
Not applicable. 
 
8.11 
Sample Collection and Handling Requirements; PGx 
Not applicable. 
 
8.12 
RADIATION THERAPY GUIDELINES 
 
Source of guidelines 
 
The information that follows is adapted from current guidelines of the 
Radiation Therapy Oncology Group (RTOG) for standard radiotherapy for 
glioblastoma in the clinical trial setting.  Much of the text is quoted directly, 
with permission. 
 
Dose Definition and Schedule 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 82 of 86 Amendment 7 version dated February 11, 2014 
 
 
Radiotherapy must begin within 35 days (5 weeks) of surgery.  One treatment 
of 2.0 Gy will be given daily 5 days per week for a total of 60.0 Gy over six 
weeks.  Treatment may be omitted on holidays, resulting in slight extension of 
the total period of treatment.  All portals shall be treated during each treatment 
session.  Treatment with a single beam is not acceptable due to unacceptable 
tumor dose inhomogeneity. 
 
Target dose definition 
Dose is specified as the target dose, which shall be the dose to the center of the 
target volume. For the following portal arrangements the target dose shall be 
specified as follows: 
 
For two opposed coaxial equally weighted beams: on the central ray at mid-
separation of beams. 
 
For an arrangement of 2 or more intersecting beams: at the intersection of the 
central ray of the beams. 
 
For complete rotation or arc therapy: in the plane of rotation at the center of 
rotation. 
 
The technique of using two opposing co-axial unequally weighted fields is not 
recommended due to unacceptable hot spots and unacceptable dose 
inhomogeneity. However, if this technique is utilized, the dose shall be 
specified at the center of the target area. 
 
Other or complex treatment arrangements: at the center of the target volume. 
 
Physical Factors 
Treatment shall be delivered with megavoltage machines of energy ranging 
from Cobalt 60 up to and including 10 MV photons. Selection of the 
appropriate photon energy(ies) should be based on optimizing the RT dose 
distribution within the target volume and minimizing dose to non-target 
normal tissue. Photon energies > 10 MV should be utilized only in dual energy 
beam arrangements using at least one beam with energy < 10 MV. Source skin 
distance for SSD techniques or source axis distance for SAD techniques must 
be at least 80 cm. Source sizes must be no more than 2 cm in Cobalt 60 
machines. For Cobalt 60 machines, secondary collimation is required. Boost 
with electrons, particles, stereotactic radiosurgery, or implants is not 
permissible. 
 
Localization, Simulation, and Immobilization 
The patient shall be treated in the supine or other appropriate position for the 
location of the lesion. A head-holding device that is transparent to x-rays must 
ensure adequate immobilization during therapy and ensure reproducibility. 
The target volume for both the initial volume and the conedown volume shall 
be based on the preoperative MRI/CT. The initial target volume shall include 
the contrast-enhancing lesion and surrounding edema (if it exists) 
demonstrated on MRI/CT plus a 2.0 centimeter margin. If no surrounding 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 83 of 86 Amendment 7 version dated February 11, 2014 
 
edema is present, the initial target volume should include the contrast-
enhancing lesion plus a 2.5 centimeter margin. 
 
This initial target volume will be treated to 46.0 Gy in 23 fractions. After 46 
Gy the conedown tumor volume should include the contrast enhancing lesion 
(without edema) on the pre-surgery MRI/CT scan plus a 2.5 centimeter 
margin. 
 
Treatment Planning 
 
Treatment plans may include opposed lateral fields, a wedge pair of fields, 
rotation, or multiple field techniques. MRI/CT-guided treatment planning is 
necessary to assure accuracy in the selection of field arrangements. 
 
 
Isodose distributions for the initial target volume and the conedown target 
volume are required on all patients, including those treated with parallel 
opposed fields. A composite plan is required showing the respective target 
volumes. The inhomogeneity across the target volume shall be kept to a 
minimum. 
 
 
The minimum dose to the target volume should be kept within 5% of the dose 
at the center of the volume.  The maximum dose should be no higher than 5% 
of the dose at the center of the target volume. 
 
Dose Limitations to Critical Structures 
 
The lens and cervical spine must be shielded from the direct beam at all times. 
When possible to do without shielding gross tumor, attempts should be made 
to limit the dose to the optic chiasm to 60 Gy, the retina of at least one eye 
(but preferably both)to 50 Gy, and the brain stem to 60 Gy.  
 
Documentation Requirements 
A copy of the pretreatment MRI/CT, the treatment prescription form, 
treatment calculation form, simulation films and representative portal films of 
each initial field must be available to be provided on request to the principal 
investigator.  At the completion of treatment, the following must also be 
available on request: daily treatment record, all isodose distributions, 
simulation and portal films of the reduced fields, and the radiotherapy 
summary. 
 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 84 of 86 Amendment 7 version dated February 11, 2014 
 
 8.13 Drugs known to be metabolized by CYP450 isoenzyme 3A4 
 
CYP3A3/4 
Substrates  
Acetaminophen 
Aifentanil 
Alosetron 
Alprazolam 
Amiodarone 
Amitriptyline (minor) 
Amlodipine 
Anastrozole 
Androsterone 
Antipyrine 
Astemizole 
Atorvastatin 
Benzphetamine 
Bepridil 
Bexarotene 
Bromazepam 
Bromocriptine 
Budesonide 
Bupropion (minor) 
Buspirone 
Busutfan 
Caffeine 
Cannabinoids 
Carbamazepine 
Cevimeline 
Cerivastatin 
Digitoxin 
Diltiazem 
Disopyramide 
Docetaxel 
Dolasetron 
Donepezil 
Doxorubicin 
Doxycycline 
Dronabinol 
Enalapril 
Erythromycin 
Estradiol 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestene 
Dofetilide (minor)  
Felodipine 
Fentanyl 
Fexotenadine 
Finaxteride 
Fluoxetine 
Flutamide 
Glyburide  
Chlorpromazine 
Cimetidine 
Cisapride 
Citałopram 
Clarithromycin 
Clindamycin 
Clomipramine 
Clonazepam 
Clozapine 
Cocaine 
Codeine (demethylation) 
Cortisol 
Cortisone 
Cyclobenzaprine (demethylation) 
Cyclophosphamide 
Cyclosporine 
Dapsone 
Dehydroepiandrostendione 
Delavirdine 
Desmethyldiazepam 
Dexamethasone 
Dextromethorphan (minor, N-demethylation)  
Diazepam (minor; hydroxylation, N-
demethylation) 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Niludipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Omeprazole (sulfonation) 
Ondansetron 
Oral contraceptives 
Orphenadrine 
Paclitaxel 
Pantoprazole 
Pimozide 
Pioglitazone 
Pravastatin 
Prednisone 
Progesterone 
Proguanil 
Propafenone 
Quercetin 
Quetiapine 
Quinidine 
Quinine 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 85 of 86 Amendment 7 version dated February 11, 2014 
 
Granisetron 
Halofantrine 
Hydrocortixone 
Hydroxyarginine 
lfosfamide 
lmipramine 
lndinavir 
lsradipine 
ltraconazole 
Ketoconazole 
Lansoprazole (minor) 
Letrozole 
Levobupivicaine 
Lidocaine 
Loratadine 
Losartan 
Lovastatin 
Methadone 
Mibefradil 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine (N-demethylation) 
Montelukast 
Navelbine 
Toremifene 
Trazodone 
Tretinoin 
Triazolam 
Troglitazone 
Troleandomycin 
Venlafaxine (N-demethylation) 
Verapamil 
Vinblastine 
Repaglinide 
Retinoic acid 
Rifampin 
Risperidone 
Ritonavir 
Salmeterol 
Saquinavir 
Sertindole 
Sertraline 
Sibutramine 
Sildenafil citrate 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Temazepam 
Teniposide 
Terfenadine 
Testosterone 
Tetrahydrocannabinol 
Theophylline 
Tiagabine 
Tolterodine 
Vincristine 
Warfarin (R-warfarin) 
Yohimbine 
Zaleplon (minor pathway) 
Zatoestron 
Zileuton 
Ziprasidone 
Zolpidem 
Zonisamide 
 
Inducers 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin  
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone  
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Inhibitors 
Amiodarone 
Anastrozole 
Azithromycin  
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
      Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 


VELCADE (bortezomib) for Injection 
 
UCLA Neuro-Oncology Program 
CONFIDENTIAL 
Page 86 of 86 Amendment 7 version dated February 11, 2014 
 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid 
ltraconazole  
 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 
 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, Armstrong 
LL, Goldman MP, Lance LL eds.  Drug Information Handbook 8th ed. Hudson, OH; 
LexiComp Inc.  2000: 1364-1371) 
                                                 
 
 

ICF_001.pdf: 
A Study of the Safety of an Experimental Drug Combined with Temozolomide
and Radiation in Individuals with Malignant Brain Tumors.
 
 




 
– 
– 
–
– 
– 
– 
– 
– 
– 
Radiation Therapy
Temozolomide
Bortezomib


–
–
–
–
Bortezomib
Temozolomide
 
– 
– 


– 
– 
– 
– 
Post Treatment Evaluation 


 
R i s k s A s s o ci a te d  wit h B o rte z o mi b:  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
u s u all y  d o e s  n ot  c a u s e  ill n e ss,  b ut  c a u s e s  di s e a s e  w h e n  a  p er s o n’ s  i m m u n e  r e s p o n s e  
 
 
 
R e p ro d u c ti v e R i s k s:  
  


your partner’s permission to collect information about her pregnancy and the health of the baby. 
Risks of Blood Sampling:
Other Side Effects:


 


 
 




 
 


B Y  SI G N IN G T H I S F O R M ,  I W IL L IN G L Y A G R E E T O  P A R T IC I PA T E  I N  T H E R E S E A R C H  IT  
D E S C R IB E S. 
  
 
 
 
a n g e s.  T h e c o nt a ct i nf or m ati o n i s i n t hi s i nf or m e d c o n s e nt f or m u n d er “I d e ntifi c ati o n 
of I n v e sti g at or s”.  
 
 
 
 
D at e ( m u st b e t h e s a m e a s s u bj e ct’ s)


A p p e n d i x A:  P ot e nt i al R i s k s an d  D i s co m f orts f or Sta n d ar d  of  C ar e 
 
Si d e E ffe c ts A s s o ci a te d  W it h T e m o z o lo mi d e : 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R i s k fro m R a d i atio n  T h er a p y :


Risks of MRI:
 
 
 
 
 


APPENDIX B:  STUDY CALENDAR 
 
Evaluation during the Radiation therapy:  
Procedures 
Prior to
Treatment 
Every Week 
Every 2-
Week 
Every 4-
Week 
At week
6 
(a)
(a)
(a)
(a)
(b)
(c)
(d)
(e)
(f)
 
 
Evaluation to be Obtained During  Bortezomib and Temozolomide after Radiation 
Procedures 
Day 1
Day 21
 
 
(b)
 
(g)
 
 
 
(a)
(b)
(c)
(d)
(e)
–
(f)
(g)