Conditions: Contiguous Stage II Mantle Cell Lymphoma Noncontiguous Stage II Mantle Cell Lymphoma Recurrent Mantle Cell Lymphoma Stage I Mantle Cell Lymphoma Stage III Mantle Cell Lymphoma Stage IV Mantle Cell Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: no

Brief summary:
RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving bortezomib together with rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving bortezomib and rituximab together works in treating patients with mantle cell lymphoma who have previously undergone stem cell transplantation

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the two year disease free survival in mantle cell lymphoma (MCL) patients treated with bortezomib + rituximab after hematopoietic stem cell transplantation (HSCT).

SECONDARY OBJECTIVES:

I. To evaluate the toxicity profile, safety, overall survival, time to treatment failure, remission duration, and biological markers of mantle cell lymphoma patients treated with bortezomib + rituximab after autologous hematopoietic stem cell transplantation.

OUTLINE: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) over 3-5 seconds and rituximab IV on days 1, 8, 15, and 22. Treatment with bortezomib repeats every 3 months for up to 8 courses and treatment with rituximab repeats every 6 months for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 3 years.

Arms:
arm 1: Doses of bortezomib given is 1.3 mg/m2 weekly x 4 weeks given every 3 month x 8 cycles. Doses of RITUXAN given is 375 mg/m2 give weekly x 4 weeks given every 6 month for 4 cycles.

Interventions: intervention 1: bortezomib intervention 2: rituximab intervention 3: laboratory biomarker analysis intervention 4: immunohistochemistry staining method intervention 5: RNA analysis intervention 6: gene expression analysis intervention 7: DNA analysis intervention 8: pharmacological study intervention 9: pharmacogenomic studies intervention 10: Questionnaire Administration
Intervention descriptions: intervention 1: Given SC or IV intervention 2: Given IV intervention 3: Correlative studies intervention 4: Correlative studies intervention 5: Correlative studies intervention 6: Correlative studies intervention 7: Correlative studies intervention 8: Correlative studies intervention 9: Correlative studies intervention 10: None

Protocol document:
Prot_SAP_000.pdf: 
IRB # 10137 
 
12/13/2018 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF Hematology/HCT 
 
 
TITLE: A PHASE II STUDY OF WEEKLY MAINTENANCE BORTEZOMIB AND RITUXIMAB IN MANTLE CELL 
LYMPHOMA S/P AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 10137  
 
VERSION: 16 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
 
COH Initial Submission           12/13/10 
 
 Version 00 
 
COH DSMB Corrections      12/28/10 
 
 
 
 
 
       Version 00 
 
COH IRB Corrections           02/23/11 
 
 
 
 
 
       Version 00 
 
COH Amend 01 
 
03/31/11 
 
 
 
 
 
       Version 01 
COH Amend 02 
 
08/11/11 
 
 
 
 
 
       Version 02 
 
COH Amend 03 
 
01/25/12 
 
 
 
 
 
       Version 03 
 
COH Amend 04 
 
07/05/12 
 
 
 
 
 
       Version 04 
 
COH Amend 05 
 
11/26/12 
 
 
 
 
 
       Version 05 
 
COH Amend 06 
 
01/15/13 
 
 
 
 
 
       Version 06 
 
COH Amend 07 
 
(Protocol dated 10/04/13, Revised DSMP) 
 
       Version 07 
COH Amend 08 
 
Personnel Change dated 12/17/13     
 
       Version 08 
COH Amend 09 
 
(Protocol dated 06/11/14, Revised Study Calendar)        Version 09 
COH Amend 10 
 
(Adding Drs. Aldoss and Pullarkat) 
 
 
       Version 10 
COH Amend 11 
 
(Adding Drs. Cao, Zain, & Mei) 
 
 
       Version 11 
COH Amend 12 
 
(Title Page - Personnel Change 9/15/14) 
 
       Version 12 
COH Amend 13 
 
(Protocol dated 11/18/2014)  
 
 
       Version 13 
COH Amend 14 
 
(Protocol dated 04/09/2015)  
 
 
       Version: 14 
COH Amend 15 
 
(Protocol dated 10/21/2015)  
 
 
       Version: 15 
COH Amend 16 
 
(Protocol dated 12/13/18) 
 
        
 
       Version: 16 
 
DISEASE SITE: 
Mantle Cell Lymphoma 
 
 
 
 
STAGE: 
 
 
 
 
 
Maintenance  
MODALITY(IES): 
 
 
 
 
Chemotherapy 
 
 
 
 
TYPE:  
 
 
 
 
 
Phase II 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Matthew Mei, M.D.  
 
 
 
 
PARTICIPATING CLINICIANS: 
 
 
Stephen Forman, M.D., Ravi Bhatia, M.D., Amrita Krishnan, M.D., 
 
 
 
 
 
 
 
Auayporn Nademanee, M.D., Ryotaro Nakamura, M.D., Margaret 
 
 
 
 
 
 
 
O’Donnell, M.D., Pablo Parker, M.D., Leslie Popplewell, M.D.,  
David Snyder, M.D., Anthony Stein, M.D., Eileen Smith, M.D., 
Chatchada Karanes, M.D., Leonard Farol, M.D., Firoozeh Sahebi, 
M.D., Ricardo Spielberger, M.D., Ji-Lian Cai, M.D., Tanya Siddiqi, 
M.D., Samer Khaled, M.D., Myo Htut, M.D., Nitya Nathwani, M.D., 
Michael Rosenzweig, M.D., Ahmed Aribi, M.D, Haris Ali, M.D., 
Amandeep Salhotra, M.D., Ibrahim Aldoss, M.D., Vinod Pullarkat, 
M.D., Thai Cao, M.D., Jasmine Zain, M.D., Alex Herrera, MD, 
Monzr Al Malki, MD and Elizabeth Budde, MD 
 
PARTICIPATING SITES: 
 
Fred Hutchinson Cancer Center  
 
Leona A. Homberg 


 
A phase II study of weekly maintenance bortezomib and rituximab in mantle cell 
lymphoma post autologous hematopoietic cell transplantation 
X05337  
Protocol Version: 
 
Date of Protocol: 
Original 
Revised for CPRMC 
Revised for DSMB 
Revised for DSMB 
Revised for IRB 
Amendment 01 
Amendment 02 
Amendment 03 
Amendment 04 
 
9/16/10 
11/22/10 
12/13/10 
12/28/10 
02/23/11 
03/31/11 
08/11/11 
01/25/12 
07/05/12 
Amendment 05 
 
11/26/12 
Amendment 06 
Amendment 07 
Amendment 08 (title page only) 
Amendment 09 
Amendment 10 (title page only) 
Amendment 11 (title page only) 
Amendment 12 (title page only) 
Amendment 13 
Amendment 14 
Amendment 15 (Administrative) 
Amendment 16 (PI Change) 
 
01/15/2013 
10/04/2013 
12/17/2013 
06/11/2014 
8/18/2014 
9/09/2014 
9/15/2014 
11/18/2014 
04/09/2015 
10/21/2015 
12/13/2018 
Investigator & Study Center: 
Matthew Mei, MD 
City of Hope National Medical Center 
1500 E. Duarte Rd, 
Duarte, CA 91010 
Telephone:  (626) 256-4673, ext 64762 
 


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Additional Investigator and Study Center 
 
Leona A. Holmberg, M.D. 
Fred Hutchinson Cancer Research Center 
1100 Fairview Ave N 
Seattle, WA 98109 
Telephone: (206) 667-4832 
 
Study Sponsor, Monitor and Data Coordinating Center:   
 
City of Hope  
 
Study Sponsor: 
 
Millennium Pharmaceuticals, Inc. 
 


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PROTOCOL SUMMARY 
Title: A phase II study of weekly maintenance bortezomib and rituximab in mantle 
cell lymphoma post autologous hematopoietic cell transplantation 
 
Objectives 
The primary objective of this study is to: 
 
Determine anti-tumor activity as assessed by disease-free survival (DFS). Estimate the two year  DFS rate 
in mantle cell lymphoma patients treated with bortezomib + rituximab after autologous hematopoietic stem 
cell transplantation. 
The secondary objectives of this study are to: 
 
To estimate the overall survival rate and evaluate time to treatment failure/remission duration. 
 
 
To describe non-relapse death events and the toxicity profile.  
 
 
Evaluate the biological markers of mantle cell lymphoma patients treated with bortezomib + rituximab after 
autologous hematopoietic stem cell transplantation. 
 
Patient population 
Refer to specific inclusion and exclusion criteria detailed in protocol. 
Number of patients 
 
36  
Study design and methodology 
 
Phase II, (Efficacy) clinical trial 
Treatments administered 
 
1) Bortezomib will be administered at a dose of 1.3 mg/m2 on D1, 8, 15, and 22 every 3 month for a total 
of 8 cycles. 
2) Rituximab will be administered at a dose of 375mg/m2 on D1, 8, 15, 22 every 6 month for a total of 4 
cycles. 
Efficacy data collected 
 
The following evaluations will be conducted to assess the efficacy of bortezomib + rituximab 
 
CT/PET or CT of neck, chest, abdomen, and pelvis will be performed every 6 months for the 1st two years 
and then yearly for the 3rd, 4th and 5th years.  


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 
Bone marrow biopsy will be performed every 6 months for the 1st  two years, then yearly thereafter 
Correlative studies collected to be done at City of Hope site only 
 
 
Peripheral blood samples will be collected at baseline and day 1 of every cycle, then every 6 months for  1st 
two years and then yearly for 3 years to examine CCND1 mRNA and isomer expression. 
 
Bone marrow sample will be collected at baseline, every 6 months for the 1st two years, then yearly for 3 
years to examine CCND1 mRNA and isomer expression. 
 
Diagnostic lymph node samples will be examined for CCND1 mRNA, isomer expression, and Ki-67. 
 
Please see section (3.5.2) for details on correlatives studies 
Safety data collected 
 
 
Specific safety measurements are detailed in section 3.6.3 and section 4. 
Statistical procedures 
 
 
Specific statistical procedures are detailed in section 5. 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION AND STUDY RATIONALE ........................................................... 11 
1.1 
Overview of the Disease ...................................................................................... 11 
1.2 
Bortezomib for Injection ...................................................................................... 12 
1.2.1 Scientific Background .............................................................................. 12 
1.2.2 Nonclinical Pharmacology ....................................................................... 13 
1.2.3 Nonclinical Toxicity ................................................................................ 13 
1.2.4 Clinical Pharmacokinetics and Pharmacodynamics ................................ 14 
1.2.5 Clinical Experience .................................................................................. 15 
1.2.6 Potential Risks of bortezomib .................................................................. 17 
 
 
1.2.7    Subcutaneous Administration of Bortezomib……...……………………22 
 
 
1.2.8    Precautions and Restrictions                                                                     23 
1.3 
RITUXAN (rituximab) for Injection ................................................................... 24 
1.3.1 Scientific Background .............................................................................. 24 
1.3.2 Pharmacology .......................................................................................... 24 
 
 
1.3.3 Formulation…………………………………………………………...…25 
 
 
1.3.4 Storage and Stability…………………………………………………….25 
 
 
1.3.5  Preparation………………………………………………………………25 
 
 
1.3.6 Route of Administration………………………………………………...25 
 
 
1.3.7 Availability and Accountability…………………………………………25 
 
 
1.3.8 Incompatibilities……………………………………………………...…25 
1.3.9 Side Effects .............................................................................................. 25 
1.4 
Study rationale and selection of drug doses ......................................................... 26 
2 
STUDY OBJECTIVES .................................................................................................... 26 
2.1 
Primary Objective ................................................................................................ 26 
2.2 
Secondary Objectives........................................................................................... 26 
3 
INVESTIGATIONAL PLAN .......................................................................................... 27 
3.1 
Overall Design and Plan of the Study .................................................................. 27 
3.2 
Selection of Patients ............................................................................................. 27 
3.2.1 Inclusion Criteria ..................................................................................... 27 
3.2.2 Exclusion Criteria .................................................................................... 28 
3.3 
Registration Processes ......................................................................................... 29 
            3.4 
Procedures for On-Study and Treatment Deviations                                           30 
 
  
3.5       Study Treatments                                                                                                 31 
3.5.1 Clinical Trial Materials ............................................................................ 30 
3.5.2 Preparation, Handling, and Storage of Drugs .......................................... 30 
 
 
3.5.3 Drug Administration and Dosing Schedule……………………………..32 
3.5.4 Dose Modification and Delay .................................................................. 34 
3.5.5 Blinding, Packaging, and Labeling .......................................................... 37 
3.5.6 Concomitant Treatment ........................................................................... 37 
3.5.7 Treatment Compliance ............................................................................. 37 
3.64 
Duration of Treatment and Patient Participation ................................................. 37 
3.7 
Efficacy, Pharmacodynamic/Pharmacogenomic/Correlative studies, and Safety 


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Measurements ...................................................................................................... 38 
3.7.1 Efficacy Measurements ............................................................................ 37 
3.7.2 Pharmacokinetic/Pharmacodynamic/Pharmacogenomic/Correlative Studies 
(optional) .................................................................................................. 39 
3.7.3 Safety Measurements ............................................................................... 40 
4 
STATISTICAL PROCEDURES ..................................................................................... 42 
4.1 
Sample Size Estimation ....................................................................................... 42 
4.2 
Randomization and Stratification ........................................................................ 43 
4.3 
Populations for Analysis ...................................................................................... 43 
4.4 
Statistical Methods ............................................................................................... 43 
 
4.5 
Protocol Deviations……………………………………………………...…...…43 
 
4.6 
Reporting of results…………………………………………………...…………43 
 
5 
Human Subject Protection……………………………………………………………….44 
 
5.1 
Data and Safety Monitoring……………………………………………………..44 
 
5.2 
Adverse events…………………………………………………………………..44 
 
 
5.2.1 Adverse Event Definition……………………………………………….45 
 
 
5.2.2 Serious Adverse Event Definition………………………………………45 
 
 
 
5.2.3 Monitoring of Adverse Events and Period of Observation………….….46 
5.3 
Millennium Definitions…………………………………………………………50   
5.4 
Participation of Children……………………………………………...…………53 
 
5.5 
Evaluation of Benefits and Risks/Discomforts…………………………………..53 
 
5.6 
Procedures for Reporting Drug Exposure During Pregnancy………………..53 
6 
ADMINISTRATIVE REQUIREMENTS ....................................................................... 54 
6.1 
Good Clinical Practice ......................................................................................... 54 
6.2 
Ethical Considerations ......................................................................................... 54 
6.3 
Patient Information and Informed Consent.......................................................... 54 
6.4 
Patient Confidentiality ......................................................................................... 54 
6.5 
Protocol Compliance ............................................................................................ 54 
6.6 
On-site Audits ...................................................................................................... 55 
6.7 
Drug Accountability............................................................................................. 55 
6.8 
Premature Closure of the Study ........................................................................... 55 
6.9 
Record Retention ................................................................................................. 55 
 
6.10    Product Complaints……………………………………………………………..55 
7 
REFERENCES ................................................................................................................ 57 
8 
APPENDICES ................................................................................................................. 60 
8.1 
Study Flow Chart ................................................................................................. 60 
8.2 
Karnofsky Performance Status Scale ................................................................... 62 
8.3 
Body Surface Area Calculation ........................................................................... 63 
8.4 
New York Heart Association Classification of Cardiac Disease ......................... 64 
8.5 
Declaration of Helsinki ........................................................................................ 65 
8.6 
Common Terminology Criteria for Adverse Events Version 4.0 ........................ 69 
8.7 
FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 ...................................... 70 


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LIST OF TABLES AND FIGURES IN THE TEXT 
Tables 
Table 1-1 
Known Anticipated Risks of Bortezomib……………………………….17  
Table 1-2 
Reports of Adverse Reactions form Postmarketing Experience……………20 
Table 3-1 
Treatment schema………………….……………………………………….29 
Table 3-2 
Dose Level schema…………,,,,,,,,,,,.………………………………………30 
Table 3-4 
Management of Patients with - Bortezomib Related Neuropathic Pain and/or Peripheral 
Sensory Neuropathy…….………………………….....................32 
Table 3-3 
Study flow chart…………………………………………………………….54 
 
 


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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 
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 Harmonization 
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 


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Abbreviation 
Definition 
m2 
square meters 
mg 
milligram 
min 
minute 
mL 
milliliter 
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 
SAE 
serious adverse event 
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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INTRODUCTION AND STUDY RATIONALE 
1.1  Overview of the Disease 
Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphoma (NHL) accounts for up to 8000 
newly diagnosed NHL cases in US and EU each year1-2.   Its hallmark is the t(11;14)(q13;q32) 
chromosomal translocation of the cyclin D1 gene (CCND1).  This results in overexpression of CCND1 
and increases cell proliferation3.  CCND1 is a regulator of cell cycle and mediates G1 to S phase 
progression4.  Although CCND1 has been found to be over expressed in other tumor types (breast, 
neuroblastoma, pancreas, multiple myeloma), the mechanism of over expression by the t(11;14)(q13;32) 
translocation is only found in MCL5.  It has been assumed that CCND1 not only promotes oncogenesis 
but also induces chemoresistance since MCL has a worse prognosis when compared to follicular 
lymphoma or diffuse large B cell lymphoma.  Indeed, standard chemotherapy regimens such as R-CHOP 
that can achieve complete remission (CR) in other NHL can only achieve CR in 34% of MCL6.  Also, 
MCL has a much higher relapse rate even if complete remission can be achieved.  Clinically, MCL 
typically presents with advanced stage disease.  The sites of disease include the lymph nodes, Bone 
marrow, spleen, peripheral blood, and the GI tract.  Patients can present with stage I (13%), stage II (7%), 
stage III (9%), or stage IV (71%).  The median age at presentation is 63 years old, and this disease favors 
men over women at a 3:1 ratio2.  Majority of the patients are elderly male patients with stage IV disease.   
 
There is no standard therapeutic regimen for MCL.  One treatment approach is the R-hyperCVAD 
regimen which includes 8 cycles of aggressive chemotherapy. The CR/CRu rate is 87%, the 3 year FFS is 
64%, and recent updates show 5 year FFS of 48%7. The disadvantages of this regimen include high 
toxicity profile, inability of patients to complete the full 8 cycles of therapy (30% of patients did not 
finish), and late relapses occur without a plateau effect.  Another treatment approach is to use autologous 
hematopoietic stem cell transplantation (AHCT) as consolidation to reduce relapse. The data ranges from 
5 year EFS of 39%, 3 year PFS of 93%, 54 month EFS of 79%, and 5 year EFS of 35%8-12.   The results 
are disappointing since relapses still occur after AHCT.  It is evident that some form of maintenance 
therapy needs to be given to try to prolong the PFS after AHCT.   
 
Bortezomib is a small molecule proteasome inhibitor that can affect multiple signaling pathways.  The 
anti-neoplastic effect of bortezomib likely involves several distinct mechanisms, including inhibition of 
cell growth and survival pathways, induction of apoptosis, and inhibition of expression of genes that 
control cellular adhesion, migration and angiogenesis.  Thus, the mechanisms by which bortezomib elicits 
its antitumor activity may vary among tumor types, and the extent to which each affected pathway is 
critical to the inhibition of tumor growth could also differ.  Indeed it has been shown to downregulate 
CCND1 expression in MCL in vitro.  It also has activity against MCL as a single agent therapy and is 
FDA approved therapy for relapsed MCL.  See section 1.2 for details on bortezomib. 
 
RITUXAN (rituximab) is a chimeric IgG monoclonal antibody targeting the CD20 surface antigen present 
on both normal lymphocytes and B-cell lymphomas.  The activity of this agent is multi-faceted, in that it 
leads to direct lysis by complement activation as well as antibody dependant cell mediated cytotoxicity, 
triggers apoptosis, and may lead to various signaling pathway changes in targeted cells (Cartron 2004).  It 
also appears to act as a chemosensitizer by blocking IL-10 binding, leading to decreased intracellular bcl-
2 (Demidem, 1997).  It has been showed to have strong activity in vitro against MCL.  This agent also has 


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clinical activity in relapsed MCL and is a standard upfront agent for all Non-Hodgkin’s Lymphoma.  See 
section 1.3 for details on RITUXAN. 
 
The combination of bortezomib + rituximab has been proven to be efficacious in the in vitro setting in 
MCL cell lines.  Alinari et al. showed that the addition of rituximab to bortezomib activated AKT 
pathways, decreased nuclear NF kappa B levels, induces apoptosis, and causes cell cycle arrest (Alinari 
2009).  There is no true phase I data of combining rituximab and bortezomib.  Both agents have been 
studied extensively in the phase I setting alone.  The toxicities are minimal and many investigators moved 
on to phase II study.  This particular combination also has been tried in Waldenstrom Macroglobulinemia 
and marginal zone lymphoma and was found to be safe and efficacious (Ghobrial 2010, de Vos 2009.)  
Dev Vos et al studied this combination in a phase II trial in marginal zone lymphoma.  He actually used a 
higher dose of 1.6 mg/m2 weekly with rituximab 375 mg/m2 weekly.  His study was published in JCO 
2009 and showed strong efficacy and minimal toxicities.  Ghobrial also used a once week dosing of 1.6 
mg/m2 weekly with rituximab 375 mg/m2 weekly to treat Waldenstrom Macroglobulinemia.  Her study is 
published in American journal of Hematology 2010 and also showed strong efficacy and minimal 
toxicities. Since our study is on for the use of maintenance after patients achieve CR, we elect to use a 
lower dose of 1.3 mg/m2 rather than 1.6 mg/m2. Since rituxan and bortezomib target different pathways 
in MCL, the combination would lead to synergy against tumor resistant pathways.   Also the toxicity 
profiles of these agents are low and relatively non interactive, which makes this combination ideal for 
study in the maintenance setting.   
 
1.2  Bortezomib for Injection 
1.2.1 Scientific Background 
Bortezomib for Injection is a small molecule proteasome inhibitor developed by Millennium 
Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies. Bortezomib is 
currently approved by the United States Food and Drug Administration (US FDA) for the treatment of 
patients with multiple myeloma (MM).  It is also indicated for the treatment of patients with mantle cell 
lymphoma (MCL) who have received at least 1 prior therapy.  In the European Union (EU), bortezomib in 
combination with melphalan and prednisone is indicated for the treatment of patients with previously 
untreated MM who are not eligible for high-dose chemotherapy with bone marrow transplant.  
Bortezomib is indicated as monotherapy for the treatment of progressive MM in patients who have 
received at least 1 prior therapy and who have already undergone or are unsuitable for bone marrow 
transplantation. 
  
By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling pathways.  
The anti-neoplastic effect of bortezomib likely involves several distinct mechanisms, including inhibition 
of cell growth and survival pathways, induction of apoptosis, and inhibition of expression of genes that 
control cellular adhesion, migration and angiogenesis.  Thus, the mechanisms by which bortezomib elicits 
its antitumor activity may vary among tumor types, and the extent to which each affected pathway is 
critical to the inhibition of tumor growth could also differ.  Bortezomib has a novel pattern of cytotoxicity 


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in National Cancer Institute (NCI) in vitro and in vivo assays (Adams et al., 1999).  In addition, 
bortezomib has cytotoxic activity in a variety of xenograft tumor models, both as a single agent and in 
combination with chemotherapy and radiation (Steiner et al., 2001; Teicher et al., 1999; Cusack et al., 
2001; LeBlanc et al., 2002; Pink et al., 2002).  Notably, bortezomib induces apoptosis in cells that over 
express bcl-2, a genetic trait that confers unregulated growth and resistance to conventional 
chemotherapeutics (McConkey et al., 1999). 
 
Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear factor B (NF-
B) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct apoptotic effect, and 
possibly anti-angiogenic and other effects (Hideshima et al., 2001). 
1.2.2 Nonclinical Pharmacology 
Pharmacokinetic (PK) and pharmacodynamic studies were conducted in the rat and cynomolgus monkey.  
Upon intravenous (IV) bolus administration, bortezomib displays a rapid distribution phase (t½ 
<10 minutes) followed by a longer elimination phase (t½ 5–15 hours).  Bortezomib has a large volume 
of distribution (range 5–50 L/kg).  The plasma PK profile is well described by a 2-compartment model. 
 
The pharmacodynamic action of bortezomib is well established and can be measured through an ex vivo 
assay (20S proteasome activity) (Lightcap et al., 2000).  This assay was used to determine the duration of 
drug effect in lieu of the PK data in the early preclinical toxicology studies as well as to set a guide for 
dose escalation in humans.  Following dosing with bortezomib in the rat and cynomolgus monkey, 
proteasome inhibition in peripheral blood had a half-life less than 24 hours, with proteasome activity 
returning to pretreatment baseline within 24 hours in monkey and within 48 to 72 hours in rat after a 
single dose of bortezomib.  Further, intermittent but high inhibition (>70%) of proteasome activity was 
better tolerated than sustained inhibition.  Thus, a twice-weekly clinical dosing regimen was chosen in 
order to allow return of proteasome activity towards baseline between dose administrations. 
1.2.3 Nonclinical Toxicity 
Single-dose IV toxicity studies were conducted with bortezomib in the mouse, rat, dog, and monkey to 
establish the single-dose maximum tolerated dose (MTD).  The MTDs were 0.25 mg/kg (1.5 mg/m2) and 
0.067 mg/kg (0.8 mg/m2) in the 2 most sensitive species, rat and monkey, respectively. 
Repeat-dose multi-cycle toxicity studies of 3 and 6 months in the rat and 9 months in the monkey, each 
with 8-week recovery periods, were conducted to characterize the chronic toxicity of bortezomib when 
administered by the clinical route and regimen of administration.  The MTD in the 6-month rat study was 
0.10 mg/kg (0.6 mg/m2) and the key target organs were the gastrointestinal (GI) tract, hematopoietic and 
lymphoid systems.  The MTD in the 9-month monkey study was 0.05 mg/kg (0.6 mg/m2) and the key 
target organs were the GI tract, hematopoietic and lymphoid systems, peripheral nervous system, and 
kidney.  Full or partial reversibility was observed for each of the toxicities described to date.   
 
In general, the nature of the toxicity of bortezomib is similar across species, and target organs of toxicity 
in animals have been largely predictive of human toxicity.  The toxicity of bortezomib in animals is 
characterized by a steep dose-response with mortality seen at dosages above the MTD.  The cause of 


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death at acutely lethal dosages is considered to be related to indirect cardiovascular (CV) effects of 
hypotension and vascular changes with secondary bradycardia and the cause of death in long-term studies 
has been attributed to GI or hematologic toxicity.  The pharmacologic effects of bortezomib on the CV 
system have been extensively characterized and have demonstrated that indirect effects on CV function 
occur only at acutely lethal dosages and are abrogated by routine supportive care. 
Additional detailed information regarding the nonclinical pharmacology and toxicology of bortezomib 
may be found in the 2006 Investigator’s Brochure 
1.2.4 Clinical Pharmacokinetics and Pharmacodynamics 
The clinical pharmacology characterization of bortezomib has been determined from phase 1 studies in 
subjects with solid tumors and hematological malignancies, and confirmed in phase 2 studies in subjects 
with multiple myeloma. 
 
Bortezomib demonstrates multi-compartmental pharmacokinetics. Following intravenous administration 
of 1.0 mg/m2 and 1.3 mg/m2 dose, the mean first-dose maximum observed plasma concentrations of 
bortezomib were 57 and 112 ng/mL, respectively in 11 patients with multiple myeloma and creatinine 
clearance values >50 mL/min participating in a pharmacokinetics study.  In subsequent doses, mean 
maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1.0 mg/m2 dose and 89 to 
120 ng/mL for the 1.3 mg/m2 dose.  The mean elimination half-life of bortezomib upon multiple dosing 
ranged from 40 to 193 hours.  Bortezomib is eliminated more rapidly following the first dose.  Mean 
Total Body Clearances were 102 and 112 L/h following the first dose for doses of 1.0 mg/m2 and 1.3 
mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1.0 and 
1.3 mg/m2, respectively.  Clinical experience has shown that the change in clearance does not result in 
overt toxicity from accumulation in this multidose regimen in humans. 
In subjects with advanced malignancies, the maximum pharmacodynamic effect (inhibition of 20S 
activity) occurred within 1-hour post dose.  At the therapeutic dose of 1.3 mg/m2 in subjects with multiple 
myeloma, the mean proteasome inhibition at 1-hour post dose was approximately 61%. 
 
The time course of proteasome inhibition in subjects is characterized by maximum inhibition observed 
within the first hour after administration, followed by partial recovery of proteasome activity over the next 
6 to 24 hours to within 50% of the pretreatment activity.  On the Day 1, 4, 8, and 11 schedule, variable 
(10%–30%) levels of proteasome inhibition have been observed at next scheduled dosing.  In theory, this 
advantage allows cells to recover proteasome activity for normal cellular housekeeping functions between 
doses. 
 
The relationship between bortezomib plasma concentrations and proteasome inhibition can be described 
by a maximum effect (Emax) model.  The Emax curve is initially very steep, with small changes in plasma 
bortezomib concentration over the range of 0.5 to 2.0 ng/mL relating to large increases in the percent 
inhibition (0–60%).  After that, a plateau occurs where marginal increases of proteasome inhibition are 
observed in spite of large changes in plasma bortezomib concentrations. 


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1.2.5 Clinical Experience  
It is estimated that as of January 2009, more than 100,000 patients have been treated with bortezomib, 
including patients treated through Millennium-sponsored clinical trials, Investigator-Initiated Studies, the 
US NCI Cancer Therapy Evaluation Program (CTEP), and with commercially available drug.  
Bortezomib has been commercially available since 13 May 2003. 
The overall goal of the Millennium phase 1 program was to determine the MTD and dose-limiting 
toxicity (DLT) of bortezomib in a number of therapeutic settings involving subjects with various 
advanced malignancies.  In a phase 1 trial in patients with refractory hematologic malignancies, the MTD 
for a twice weekly dosing for 4 weeks of a 42-day cycle was 1.04 mg/m2/dose, with DLTs of 
thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise.1  The toxicity was greatest during 
the third and fourth weeks of therapy.  In the 3-week schedule of bortezomib monotherapy (4 doses, given 
on Days 1, 4, 8, and 11 of a 21-day treatment cycle), the DLT occurred at 1.56 mg/m2/dose (3 subjects 
with Grade 3 diarrhea and 1 with peripheral sensory neuropathy).  Therefore, the MTD at this schedule 
was 1.3 mg/m2/dose.  In a 35-day treatment cycle with 4 weekly doses of bortezomib monotherapy, the 
MTD was 1.6 mg/m2/dose and DLT included hypotension, tachycardia, diarrhea, and syncope. 
In phase 1 clinical studies, antitumor activity was reported in subjects with Non-Hodgkin’s Lymphoma 
(NHL), MM, Waldenström’s Macroglobulinemia, squamous cell carcinoma of the nasopharynx, 
bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate cancer.2,3,4,5 
The safety and efficacy of bortezomib in subjects with MM were investigated in two phase 2 clinical 
studies, studies M34100-024 (subjects with first relapse)6 and M34100-025 (subjects with second or 
greater relapse and refractory to their last prior therapy).7  In M34100-025, 202 heavily pretreated subjects 
with refractory MM after at least 2 previous treatments received bortezomib, 1.3 mg/m2 on Days 1, 4, 8, 
and 11 of a 21-day treatment cycle.  The European Group for Blood and Marrow Transplant (EBMT) 
response criteria, as described by Blade8 were utilized to determine disease response.  Complete responses 
(CRs) were observed in 4% of subjects, with an additional 6% of patients meeting all criteria for CR but 
having a positive immunofixation test.  Partial response (PR) or better was observed in 27% of subjects, 
and the overall response rate (CR, PR, and minor response [MR] combined) was 35%.  Seventy percent of 
subjects experienced stable disease or better. 
The phase 3 study (M34101-039)9, also referred to as the APEX study, was designed to determine 
whether bortezomib provided benefit (time to progression [TTP], response rate, and survival) to patients 
with relapsed or refractory MM relative to treatment with high-dose dexamethasone.  The study was also 
designed to determine the safety and tolerability of bortezomib relative to high-dose dexamethasone, and 
whether treatment with bortezomib was associated with superior clinical benefit and quality of life 
relative to high-dose dexamethasone.  A total of 669 patients were enrolled and 663 patients received 
study drug (bortezomib:  331; dexamethasone:  332).  Patients randomized to bortezomib received 1.3 
mg/m2 IV push twice weekly on Days 1, 4, 8, and 11 of a 3-week cycle for up to 8 treatment cycles as 
induction therapy, followed by 1.3-mg/m2 bortezomib weekly on Days 1, 8, 15, and 22 of a 5-week cycle 
for 3 cycles as maintenance therapy.  Patients randomized to dexamethasone received oral dexamethasone 
40 mg once daily on Days 1 to 4, 9 to 12, and 17 to 20 of a 5-week cycle for up to 4 treatment cycles as 


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induction therapy, followed by dexamethasone 40 mg once daily on Days 1 to 4 of a 4-week cycle for 
5 cycles as maintenance therapy.  The EBMT response criteria were utilized to determine disease 
response.  There was a 78% increase in TTP for the bortezomib arm.  Median TTP was 6.2 months for the 
bortezomib arm and 3.5 months for the dexamethasone arm (p < 0.0001).  CR + PR was 38% with 
bortezomib versus 18% with dexamethasone (p  0.0001).  CR was 6% with bortezomib versus  1% 
with dexamethasone (p < 0.0001).  The CR + nCR (near CR) rate was 13% with bortezomib versus 2% 
with dexamethasone.  In patients who had received only 1 prior line of treatment (bortezomib:  132; 
dexamethasone:  119), CR + PR was 45% with bortezomib vs 26% with dexamethasone (p = 0.0035).  
With a median 8.3 months of follow-up, overall survival was significantly longer (p = 0.0013) for patients 
on the bortezomib arm versus patients on the dexamethasone arm.  The probability of survival at 1 year 
was 80% for the bortezomib arm versus 66% for the dexamethasone arm, which represented a 41% 
decreased relative risk of death in the first year with bortezomib (p = 0.0005).  In patients who had 
received only 1 prior line of treatment, the probability of survival at 1 year was 89% for the bortezomib 
arm versus 72% for the dexamethasone arm, which represented a 61% decreased relative risk of death in 
the first year with bortezomib (p = 0.0098).  Updated response rates and survival data were reported for 
M34101-039.10  The updated CR + PR rate was 43% with bortezomib.  The CR + nCR rate was 16% with 
bortezomib.  With a median 22 months of follow-up, overall survival was significantly longer for patients 
on the bortezomib arm versus patients on the dexamethasone arm.  The median overall survival was 
29.8 months (95% CI:  23.2, not estimable) for the bortezomib arm vs 23.7 months (95% CI:  18.7, 29.1) 
for the dexamethasone arm (hazard ratio = 0.77, p = 0.0272).  The probability of survival at 1 year was 
80% for the bortezomib arm versus 67% for the dexamethasone arm (p = 0.0002). 
The safety and efficacy of bortezomib in relapsed or refractory mantle cell lymphoma (MCL) were 
investigated in an international, phase 2, multicenter study M34103-053, also referred to as the 
PINNACLE study.11  The single-arm study was designed to evaluate the response rates, duration of 
response (DOR), TTP, overall survival (OS), and safety of bortezomib treatment in patients with relapsed 
or refractory mantle cell lymphoma.  For 141 evaluable patients, the response rate was 31% (8% 
CR/unconfirmed CR [Cru]).  Median time to response was 40 days (range 31-204 days).  The median 
number of cycles administered across all patients was 4; in responding patients, the median number of 
cycles was 8.  The median DOR by algorithm was 9.2 months and 13.5 months in patients with CR/CRu.  
Median TTP for both groups was 6.2 months.  With a median follow-up of 13.4 months, overall survival 
had not been reached.  The most commonly reported adverse events (AEs) were fatigue, peripheral 
neuropathy, and gastrointestinal events.  A time-to-event update to the PINNACLE study12 was reported 
after a median follow-up of 26.4 months.  TTP was 6.7 months for all patients, 12.4 months in all 
responders.  The median DOR was 9.2 months in all responders and had not been reached in patients 
achieving CR/Cru.  Overall survival was 23.5 months in all patients and 36 months in patients with 
CR/Cru.  Survival at 12 months was 69% overall and 91% in responding patients. 
The phase 3 study (MMY 3002) known as the VISTA study, evaluated the safety and efficacy of the 
combination of bortezomib, melphalan, and prednisone in previously untreated multiple myeloma patients 
who were not candidates for stem cell transplant.13  The study was designed to determine the benefit of 
adding bortezomib to MP (melphalan and prednisone) as assessed by TTP.  Patients (682) were 


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randomized to receive nine 6-week cycles of melphalan 9mg/m2 and prednisone 60 mg/m2 on Days 1 to 4, 
alone or in combination with bortezomib 1.3 mg/m2 by IV bolus on Days 1, 4, 8, 11, 22, 25, 29, and 32 
during Cycles 1 to 4, and on Days 1, 8, 22, and 29 during Cycles 5 to 9.  Response was evaluated every 3 
weeks using the EBMT criteria.  At a preplanned interim analysis, the independent data monitoring 
committee recommended that the study be stopped since the prespecified statistical boundary end point of 
TTP had been crossed.  Response rates were 30% with 4% CR.  The rates of partial response or better 
were 71% in the bortezomib (VMP) group compared to 34% in the MP group (p = 0.001).  With follow-
up of 16.3 months, the TTP for the VMP group was 24 months compared to 16.6 months in the MP group 
(p = 0.000001) and was associated with a 52% reduced time to progression.  The median DOR was 19.9 
months in the VMP group and 13.1 months in the MP group.  Overall survival had not been reached in 
either group.  Hematologic toxicity was similar in both groups.  The incidence of peripheral sensory 
neuropathy and gastrointestinal symptoms was higher in the VMP group.  The incidence of herpes zoster 
was 3% in patients in the VMP group who received antiviral prophylaxis.  Fifteen percent of patients in 
the VMP group discontinued therapy due to AEs compared to 14% in the MP group. 
The VISTA study update after extended follow-up of 25.9 months,14 confirmed a survival benefit for the 
VMP group.  Overall survival was not reached in either group:  VMP group (75) deaths, 3 year OS 72%; 
MP group (111) deaths, 3 year OS 59% (p = 0.0032).  Patients on VMP were less likely to start second-
line therapy (VMP 38% vs MP 57% at the time of data cut-off) with a longer time to next therapy (TNT) 
and treatment free interval (TFI).  Of the MP patients who received subsequent therapy, 43% went on to 
receive bortezomib. 
Based on investigator-reported best responses to subsequent therapies, patients relapsing after therapy 
with a novel agent were not intrinsically more resistant than after receiving a traditional agent. 
In the VISTA study, VMP was associated with prolonged TTP, TNT, TFI, and OS.  Patients were 
successfully treated with subsequent IMiD-based therapy and retreated with bortezomib.  After 36.7 
months follow-up, OS continued to be superior for VMP.  The OS for VMP had not yet been reached 
compared to MP (43.1 months).15 
 
1.2.6 Potential Risks of Bortezomib 
To date, more than 100,000 patients have been treated with bortezomib in both clinical trials investigating 
its use in hematological malignancies and solid tumors, and in patients who were treated with 
commercially available bortezomib. 
Prescribing physicians and health care practitioners are referred to their locally approved product label for 
bortezomib regarding Indications and Usage, Contraindications, Warnings, and Precautions. 
The known anticipated risks of bortezomib therapy are presented in Table 0-1  and Table 0-12.  These 
risks are grouped according to the combined frequency observed in an integrated analysis of AEs in 
sponsored clinical studies of single-agent bortezomib dosed at 1.3 mg/m2 twice weekly on a 21-day 
schedule, in patients with multiple myeloma and mantle cell lymphoma. 
 


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Table 0-1    
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Blood and Lymphatic System Disorders 
Most common 
Thrombocytopenia*, anaemia* 
Very common  
Neutropenia* 
Common  
Lymphopenia, pancytopenia*, leukopenia*, febrile 
neutropenia 
Cardiac Disorders 
Common  
Tachycardia, atrial fibrillation, palpitations, cardiac 
failure congestive* 
Uncommon 
Cardiogenic shock*, atrial flutter, cardiac tamponade*, 
bradycardia, atrioventricular block complete, arrhythmia, 
cardiac arrest, cardiac failure, arrhythmia, pericardial 
effusion, pericarditis, pericardial disease, 
cardiopulmonary failure 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impaired 
Eye Disorders 
Common  
Blurred vision, conjunctivitis, conjunctival haemorrhage  
Gastrointestinal Disorders 
Most common 
Constipation, diarrhoea*, nausea, vomiting* 
Very common  
abdominal pain (excluding oral and throat) 
Common  
Dyspepsia, pharyngolaryngeal pain, gastroesophageal 
reflux, abdominal distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal haemorrhage*, 
lower gastrointestinal haemorrhage*± rectal 
haemorrhage 
Uncommon 
Eructation, gastrointestinal pain, tongue ulceration, 
retching, upper gastrointestinal haemorrhage*, 
haematemesis*, oral mucosal petechiae, ileus paralytic*, 
ileus, odynophagia, enteritis, colitis, oesophagitis, 
enterocolitis, diarrhoea haemorrhagic, acute 
pancreatitis*, intestinal obstruction 
General Disorders and Administration Site Conditions 
Most common 
Fatigue, pyrexia 
Very common  
Chills, oedema peripheral, asthenia 
Common  
Neuralgia, lethargy, malaise, chest pain, mucosal 
inflammation* 
Uncommon 
Injection site pain, injection site irritation, injection site 
phlebitis, general physical health deterioration*, 
catheter-related complication 


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Table 0-1    
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Hepatobiliary Disorders 
Uncommon 
Hyperbilirubinaemia, hepatitis* 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 
Infections and Infestations 
Very common  
Upper respiratory tract infection, nasopharyngitis, 
pneumonia*, Herpes zoster* 
Common  
Lower respiratory tract infection*, sinusitis, pharyngitis, 
oral candidiasis, urinary tract infection*, sepsis, 
bactaeremia*, cellulitis, Herpes simplex, bronchitis, 
gastroenteritis*, infection 
Uncommon 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung infection, 
infusion site cellulitis, catheter site cellulitis, infusion 
site infection, urosepsis*, Aspergillosis*, tinea infection, 
Herpes zoster ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic, varicella, empyema, 
fungal oesophagitis 
Injury, Poisoning, and Procedural Complications  
Common 
Fall 
Uncommon 
Subdural haematoma 
Investigations 
Common  
Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, 
blood alkaline phosphatase increased, liver function test 
abnormal, blood creatinine increased* 
Uncommon 
Gamma-glutamyltransferase (GGT) increased, oxygen 
saturation decreased*, blood albumin decreased, ejection 
fraction decreased* 
Metabolism and Nutritional Disorders 
Very common  
Decreased appetite, anorexia, dehydration* 
Common  
Hyperglycaemia, hypoglycaemia, hyponatraemia, 
hypokalaemia, hypercalcaemia* 
Musculoskeletal and Connective Tissue Disorders 
Very common  
Bone pain, myalgia, arthralgia, back pain 
Common 
Muscular weakness 
Uncommon 
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon 
Tumour lysis syndrome* 


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Table 0-1    
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Nervous System Disorders 
Most common 
Peripheral neuropathy (including all preferred terms 
under the MedDRA High-level term Peripheral 
neuropathy NEC) 
Very common  
Paresthesia, dizziness excluding vertigo, headache 
Common  
Polyneuropathy, syncope, dysesthesia, dysgeusia, 
postherpetic neuralgia 
Uncommon 
Convulsion, loss of consciousness, ageusia, 
encephalopathy, paralysis*,autonomic neuropathy, 
reversible posterior leukoencephalopathy syndrome 
Psychiatric Disorders 
Very common 
Anxiety, insomnia  
Common 
Confusional state  
Uncommon 
Delirium 
Renal and Urinary Disorders 
Common 
Renal impairment*, renal failure*, haematuria 
Uncommon 
Micturition disorder 
Respiratory, Thoracic, and Mediastinal Disorders 
Very common 
Cough, dyspnoea  
Common 
Epistaxis, dyspnoea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary oedema 
Uncommon 
Hemoptysis*, acute respiratory distress syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar haemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, pleuritic 
pain 
Skin and Subcutaneous Tissue Disorders 
Very common 
Rash 
Common 
Rash pruritic, rash erythematous, urticaria, petechiae 
Uncommon 
Cutaneous vasculitis, leukocytoclastic vasculitis  
Vascular Disorders 
Common 
Hypotension*, orthostatic hypotension 
Uncommon 
Cerebral haemorrhage* 
Source:  BortezomibInvestigator’s Brochure Edition 14. 
Most common =  30%, Very common = 10% to 29%, Common = 1% to 9%, Uncommon = < 1%. 
* Fatal outcomes have been reported. 
 Indicates a Preferred term not listed in the source table, however the event is deemed medically important 
and so is included. 


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Table 0-2    
Reports of Adverse Reactions From 
Postmarketing Experience 
System Organ Class 
 
Preferred Term 
Observed 
Incidencea 
Blood and lymphatic system disorders 
 
 
Disseminated intravascular coagulation  
Rare 
Cardiac Disorders 
 
 
Atrioventricular block complete 
Rare 
 
Cardiac tamponade 
Rare 
Ear and labyrinth disorders 
 
 
Deafness bilateral 
Rare 
Eye Disorders 
 
 
Ophthalmic herpes 
Rare 
Gastrointestinal Disorders 
 
 
Acute pancreatitis  
Rare 
 
Ischemic colitis 
Rare 
Hepatobiliary disorders 
 
 
Hepatitis 
Uncommon 
 
Liver failure 
Unknown 
Infections and infestations 
 
 
Herpes meningoencephalitis 
Rare 
 
Septic shock 
Rare 
Immune System Disorders 
 
 
Angioedema 
Rare 
Nervous System Disorders 
 
 
Autonomic neuropathy 
Rare 
 
Dysautonomia 
Unknown 
 
Encephalopathy 
Rare 
Respiratory, thoracic and mediastinal disorders: 
 
 
Acute diffuse infiltrative pulmonary diseaseb  
Rare 
 
Acute respiratory distress syndrome (ARDS) 
Rare 
 
Interstitial pneumonia 
Rare 
 
Lung infiltration 
Rare 
 
Pneumonitis 
Rare 
 
Pulmonary hypertension 
Rare 


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Table 0-1    
Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Skin and subcutaneous system disorders 
 
 
Acute febrile neutrophilic dermatosis 
Unknown 
 
Toxic epidermal necrolysis 
Unknown 
Eye Disorders 
 
Ophthalmic herpes 
Rare 
Optic neuropathy 
Rare 
Blindness 
Rare  
Source:  Bortezomib Investigator’s Brochure Edition 14. 
a Incidence is assigned using the following convention:  very common 
( 1/10); common ( 1/100 and  1/10); uncommon ( 1/1000 and 
 1/100); rare ( 1/10,000 and  1/1000 ); very rare ( 1/10,000, 
including isolated reports). 
b Acute diffuse infiltrative pulmonary disease is a MedDRA Lower 
Level Term which corresponds to a Preferred Term of Interstitial lung 
disease. 
 
Other medical events of interest that are considered not causally related to include hepatic failure and QT 
prolongation.  Fatal outcomes have been reported. 
Women of childbearing potential should avoid becoming pregnant while being treated with Bortezomib.  
Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames assay and in the in vivo 
micronucleus assay, but it is a clastogen in the in vitro chromosomal aberration assay. 
Additional details on the potential risks of bortezomib may be found in the current Investigator’s 
Brochure. 
 
1.2.7 Subcutaneous administration of Bortezomib 
 
Subcutaneous administration of has been investigated in two clinical trials in MM (multiple myeloma), 
including MMY-3021, a phase III, randomized, open-label, prospective study of subcutaneous (SC) vs. 
intravenous (IV) administration of bortezomib in patients with relapsed MM.  Subcutaneous 
administration of bortezomib has not been approved by the FDA. 
 


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Moreau et al published a phase I trial of SC vs. IV bortezomib in relapsed MM in Hematologicae 2008. 
93(12):1908-11.  This trial showed the response rate was similar between the IV vs. SC arm and area 
under the curve was also similar.    
 
In 2008, Moreau et al. first described the subcutaneous administration of bortezomib in a group of 
patients with multiple myeloma (MM).  At the 2010 annual meeting of the American Society of 
Hematology (ASH), this group presented data from a phase III randomized controlled trial comparing 
intravenous and subcutaneous routes of administration of bortezomib with or without dexamethasone in 
patients with MM. Randomized, Phase 3 study compared the efficacy and safety of subcutaneous versus 
intravenous bortezomib at the approved 1·3 mg/m(2) dose and twice per week schedule in patients with 
relapsed multiple myeloma. 222 patients were randomly assigned to receive subcutaneous (n=148) or 
intravenous (n=74) bortezomib. The response-evaluable population consisted of 145 patients in the 
subcutaneous group and 73 in the intravenous group.Patients received a median of eight cycles (range one 
to ten) in both groups.  
ORR after four cycles was 42% in both groups (61 patients in subcutaneous group and 31 in intravenous 
group; ORR difference -0·4%, 95% CI -14·3 to 13·5), showing non-inferiority (p=0·002). After a median 
follow-up of 11·8 months (IQR 7·9-16·8) in the subcutaneous group and 12·0 months (8·1-15·6) in the 
intravenous group, there were no significant differences in time to progression (median 10·4 months, 95% 
CI 8·5-11·7, vs 9·4 months, 7·6-10·6; p=0·387) and 1-year overall survival (72·6%, 95% CI 63·1-80·0, 
vs 76·7%, 64·1-85·4; p=0·504) with subcutaneous versus intravenous bortezomib.  
Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group versus 52 
(70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 14 [19%]), 
neutropenia (26 [18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral neuropathy of any 
grade (56 [38%] vs 39 [53%]; p=0·044), grade 2 or worse (35 [24%] vs 30 [41%]; p=0·012), and grade 3 
or worse (nine [6%] vs 12 [16%]; p=0·026) was significantly less common with subcutaneous than with 
intravenous administration. Subcutaneous administration was locally well tolerated.  
Subcutaneous bortezomib offered non-inferior efficacy to standard intravenous administration, with an 
improved safety profile. 
 
  1.2.8  Precautions and Restrictions 
It is not known what effects bortezomib has on human pregnancy or development of the embryo or fetus.  
Therefore, female patients participating in this study should avoid becoming pregnant, and male patients 
should avoid impregnating a female partner.  Nonsterilized female patients of reproductive age and male 
patients should use effective methods of contraception through defined periods during and after study 
treatment as specified below. 
Female patients must meet 1 of the following: 
 Postmenopausal for at least 1 year before the screening visit, or 


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 Surgically sterile, or 
 If they are of childbearing potential, agree to practice 2 effective methods of contraception from 
the time of signing the informed consent form through 30 days after the last dose of bortezomib, 
or agree to completely abstain from heterosexual intercourse. 
It is strongly recommended that at least 1 of these 2 methods be highly effective (see examples below). 
Highly effective methods 
Other effective methods (barrier methods) 
Intra-uterine devices (IUD) 
Latex condom 
Hormonal contraceptives (birth control pills/oral 
contraceptives, injectable contraceptives, 
contraceptive patches, or contraceptive implants) 
Diaphragm with spermicide 
Cervical cap 
Sponge 
If one of the highly effective methods cannot be used, using 2 effective methods at the same time is 
recommended.  
 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the following: 
 Practice effective barrier contraception during the entire study treatment period and through a 
minimum of 30 days after the last dose of study drug, or completely abstain from heterosexual 
intercourse. 
1.3  RITUXIMAB (rituximab) for Injection 
1.3.1 Scientific background:   
Rituximab is a chimeric IgG monoclonal antibody targeting the CD20 surface antigen present on both 
normal lymphocytes and B-cell lymphomas.  The activity of this agent is multi-faceted, in that it leads to 
direct lysis by complement activation as well as antibody dependant cell mediated cytotoxicity, triggers 
apoptosis, and may lead to various signaling pathway changes in targeted cells (Cartron 2004).  It also 
appears to act as a chemosensitizer by blocking IL-10 binding, leading to decreased intracellular bcl-2 
(Demidem, 1997).  This suggests that rituximab may synergize with bortezomib.  It is reasonable to 
combine the two agents, bortezomib and rituximab, in MCL.   
This combination has already been used in previous phase II trials for relapsed MCL with good results.  It 
was well tolerated for MCL patients.   
1.3.2 Pharmacology: 
Kinetics:  In prior studies patients treated at the 375mg/m2 dose levels exhibited detectable antibody 
concentrations throughout the treatment period.  Most patients exhibited increasing pre-infusion antibody 
concentrations with each subsequent infusion.  In nine patients, the T1/2 following the first antibody 
infusion was 59.8 hours (11.1-104.6 hr) with a C max of 271g/ml.  Following the fourth antibody infusion 
when circulating B cells had been depleted and antigentic sites coated, the T1/2 was 174 hrs (26.4-442.3 
hr) and C max 496.7 g/ml. 


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  1.3.3 Formulation:   
Rituximab antibody will be provided in 100 mg (10ml) and 500 mg (50 ml) vials at a concentration of 
10.0 mg of protein per mL. 
  1.3.4 Storage and stability:  
Stored at 2-8.  Reconstituted antibody is stable for 24 hours upon refrigeration followed by 12 hours at 
room temperature. 
1.3.5 Preparation:  
Diluted with normal saline to a concentration of 1-4 mg/ml.  Shaking can cause aggregation and 
precipitation fo the antibody and should be avoided. 
1.3.6 Route of Administration:  
Intravenous 
1.3.7 Availability and Accountability:  
Rituximab is commercially available in 10 mL (100mg) and 50 mL (500mg) single-use vials at a 
concentration of 10mg/mL.  Use of rituximab is considered standard care for this indication, and will not 
be provided by Millennium. 
1.3.8  Incompatibilities 
Do not mix or dilute rituximab with other drugs.  No incompatibilities between rituximab and 
polyvinylchloride or polyethylene bags have been observed. 
1.3.9 Side effects 
1. Infusion related symptoms: Fever, chills, rigors, hypotension, anaphylaxis or hypersensitivity 
reactions, arrhythmia, dyspnea, bronchospasm, angioedema.  In rare cases, severe and fatal 
cardiopulmonary events, including hypoxia, pulmonary infiltrates, acute respiratory distress 
syndrome, myocardial infarction, and cardiogenic shock, have occurred.  (4-7/10,000 patients 
or 0.04-0.07%).  Nearly all fatal infusion-related events occurred in association with the first 
infusion.  Patients with pre-existing cardiac conditions, including arrhythmia and angina, have 
had recurrences of these cardiac events during rituximab infusions. 
2. Gastrointestinal: Nausea, vomiting. 
3. Hematologic: Leukopenia, anemia, thrombocytopenia.  In clinical trials, NCI CTC Grade 3 and 
4 cytopenias were reported in 48% of patients treated with rituximab; these include: 
lymphopenia (40%), neutropenia (6%), leucopenia (4%), anemia (3%), and thrombocytopenia 
(2%). The median duration of lymphopenia was 14 days (range, 1 to 588 days) and of 
neutropenia was 13 days (range, 2-116 days).   A single occurrence of transient aplastic anemia 
(pure red cell aplasia) and two occurrences of hemolytic anemia following rituximab therapy 
was reported.   


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4. Dermatologic: Rash, pruritus, urticaria, and rarely severe mucocutaneous reactions 
5. Infectious: Reactivation of hepatitis B; reactivation of other viral infections or increased 
susceptibility to other infections.  Hepatitis B virus (HBV) reactivation with fulminant 
hepatitis, hepatic failure, and death has been reported in some patients with hematologic 
malignancies treated with rituximab.  The majority of patients received rituximab in 
combination with chemotherapy.  The median time to diagnosis of hepatitis was approximately 
four months after the initiation of rituximab and approximately one month after the last dose. 
 
1.4  Study rationale and selection of drug doses 
Doses of RITUXAN given is 375 mg/m2 give weekly x 4 weeks given every 6 month for 4 cycles.  This 
is the standard maintenance dosing regimen used for follicular lymphoma and for mantle cell lymphoma.   
Doses of bortezomib given is 1.3 mg/m2 weekly x 4 weeks given every 3 month x 8 cycles.  Doses of 1.3 
mg/m2 is based on prior pharmacokinetics study.  Dosing schedule is changed from D1, 4, 8, 11 to D 1, 8, 
15, and 22 to allow for recovery of normal healthy tissues in post transplant patients to avoid toxicity 
since this will be a maintenance study.  Prior studies have also combined bortezomib + RITUXAN and 
proved no additional toxicities13-14.  We have chosen to use the subcutaneous route of administration 
instead of intravenous route because of increased convenience for patients (this is a maintenance study 
and patients will likely prefer subcutaneous administration due to less time spent in clinic).  Also based on 
the ASH 2010 presentation there appears to be less grade > 3 AEs and peripheral neuropathy associated 
with SC administration.   
 
 
2 
STUDY OBJECTIVES 
  2.1 Primary Objective 
The primary objective of this study is to evaluate the two year disease free survival in MCL patients 
treated with bortezomib + rituximab after HSCT 
 
  2.2 Secondary Objectives 
Evaluate the toxicity profile, safety, overall survival, time to treatment failure, remission duration, and 
biological markers of mantle cell lymphoma patients treated with bortezomib + rituximab after autologous 
hematopoietic stem cell transplantation. 
 
 
 


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3 INVESTIGATIONAL PLAN 
  3.1 Overall Design and Plan of the Study 
This is an open label, phase II study of maintenance bortezomib + RITUXAN in patients with mantle cell 
lymphoma s/p autologous hematopoietic stem cell transplantation (AHCT).  Patients must have achieved 
engraftment by D60-180 as evidenced by ANC >1000 and Plt > 80K.  Patients also must not have greater 
than grade 1 peripheral neuropathy at the time of starting bortezomib.  Patients will start the screening 
process at D60 to D180 after AHCT to make sure they qualify for study.  Patients need to be in complete 
remission by D60 to D180 as evidenced by either CT scan of the neck, chest, abdomen, and pelvis, or by 
CT/PET scan, and by bone marrow biopsy.  Patients will then start treatment with bortezomib + 
RITUXAN as maintenance therapy within D60-D180 after AHCT.  Bortezomib will be given at a dose of 
1.3 mg/m2 on D1, 8, 15, 22 in a 28 day period every 3 months for a total of 8 cycles.  RITUXAN will be 
given at dose of 375 mg/m2 on D1, 8, 15, 22 in a 28 day period every 6 months for a total of 4 cycles.   
The primary efficacy endpoint of this study is two year disease free survival.  This is a phase II efficacy 
trial.  Response will be assessed according to modified criteria for malignant lymphoma, based on 
(Cheson et al 1999) and (Cheson, et al 2007).  For the 1st two years of treatment, assessments will be 
performed at every cycle.  After treatment period, assessments will be performed every 6 months for three 
additional years. Patients will then undergo end of treatment assessment at year five.  Clinical suspicion 
of disease relapse at any time will require a physical examination and radiological confirmation to be 
performed promptly, rather than waiting for the next scheduled radiological assessment.   
  3.2 Selection of Patients 
The total number of patients to be enrolled on this study is 36. (25 from COH and 11 at Fred Hutchinson 
Cancer Research Center) 
 
Enrollment is defined as the first day of bortezomib treatment (i.e., Day 1 of Cycle 1). 
3.2.1 Inclusion Criteria  
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
 Patients must have histological documented or cytological confirmed Mantle Cell Lymphoma.  Cyclin 
D1 must be present as evidenced by either FISH or Immunohistochemical staining.   
 Patients must have undergone AHCT and achieved engraftment by D60-180 as evidenced by ANC 
>1000/mcL and Plt > 75,000/mcL. 
 Patients must be in complete remission at D60-180 after AHCT as evidenced by CT scan of the 
neck/chest/abd/pelvis or CT/PET scans. 
 Voluntary written informed consent 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. 
 Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable 
method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with 
spermicide, condom with spermicide, or abstinence) for the duration of the study. 


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 Male subject agrees to use an acceptable method for contraception for the duration of the study. 
 Age > 18 years old.  Because no dosing or adverse event data are currently available on the use of 
bortezomib in patients < 18 years of age, children are excluded from this study but will be eligible for 
future pediatric single-agent trials, if applicable.   
 Life expectancy of greater than 3 months. 
 Karnosfsky > 60%. 
 Patients must have normal organ and marrow function as defined below: 
o ANC > 1000/mcL 
o Plts > 75,000/mcL 
o Total bilirubin within normal institutional limits, patients with elevation of unconjugated 
bilirubin alone, as in Gilbert’s disease, are eligible. 
o AST/ALT < 2.5 X institutional upper limit of normal. 
o Creatinine up to and including 2 mg/dL. 
3.2.2 Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study. 
 
 Patient has Grade 2 peripheral neuropathy within 14 days before enrollment and at D60-180 after 
AHCT.  Patients who had > Grade 2 peripheral neuropathy within 14 days before enrollment but 
resolves to grade 1 or lower peripheral neuropathy at D60-D180 after AHCT can be enrolled at this 
time. 
 Patient has >1.5 x ULN Total Bilirubin unless history of Gilbert’s syndrome. 
 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. 
 Patient has received other investigational drugs with 14 days before treatment of treatment with 
bortezomib + rituximab 
 Serious medical or psychiatric illness likely to interfere with participation in this clinical study. 
 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, or low-risk prostate cancer after curative therapy.   
 Patients with other active malignancies (no evidence of other cancer or life expectancy greater than 5 
years) are ineligible for this study.   


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 HIV positive patients or Hepatitis B or C positive patients due to risk of reactivation from marrow-
suppressive therapy and Rituximab. 
 Patients with active CNS disease or history of brain mets are excluded from study. 
 Prior exposure to either bortezomib or rituximab is not an exclusion criteria. 
 
Eligible patients will be given the opportunity to participate in the study. The goals of the study will be 
described and the patient will be given a copy of the informed consent to review. The interested patient 
will sign the consent form and retain a copy.  
 
3.3 Registration Processes 
 
Registration Process (City of Hope patients) 
 
o Registrations for this protocol must be made through the CTO office at the City of 
Hope between the hours of 8:30 a.m. to 4:30 p.m., Monday through Friday (except 
holidays).   
o Patients must be registered prior to initiation of protocol therapy.   
o A patient failing to meet all protocol requirements may not be registered.  If you have 
any questions regarding eligibility, contact (626) 256-4673 ext. 62468 and ask for the 
CRA in charge of this study.  
o Prestudy laboratory tests, scans and x-rays must be completed prior to registration 
according to the study calendar.  
o Patients must sign an informed consent prior to registration.  
o Confirm that the patient meets all inclusion and exclusion eligibility criteria for the 
protocol.  
o Completion of the Eligibility Checklist (per institutional guidelines).  
o Verify that all required prestudy tests were performed.   
o Fax the completed Eligibility Checklist and the signed, dated informed consent to 
CTO.  The FAX number is (626) 301-8393.    
o Call CRA at (626) 256-4673 x 62468 to confirm the FAX arrival. If the CRA is not in 
the office, have him/her paged.   
o If the patient qualifies, the CRA will assign the patient's study ID number. 
o Once a patient has been registered, CRA will confirm registration of the patient.  
 
The outside institution patient registration process will be handled by the Department of Clinical 
Research Information Support (CRIS) Data Coordinating Center (DCC) at City of Hope.  
Documentation of current IRB approval must be on file with the DCC prior to registration of 
patients on this study for participating institutions.  
  
The steps below are to be taken when registering a patient at a participating institution: 
 
Registration Process (Participating Institutions) 
 


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o The participating institution’s research staff must assure they have the most current 
and updated version of the protocol and informed consent prior to enrolling a 
patient.  If a question arises, please contact the Data Coordinating Center at 626-256-
4673 extension 63968 or via pager at 626-423-6486.   
o The participating institution must assure that all prestudy laboratory tests, scans and 
x-rays have been completed prior to registration according to the study calendar.   
o The participating institution must assure that the patient has signed an approved 
informed consent prior to registration, including Experimental Subject Bill of Rights 
(if applicable) and appropriate HIPAA authorization.   
o The participating institution must confirm that the patient meets all inclusion and 
exclusion eligibility criteria for a protocol.  The eligibility checklist must be completed 
in its entirety.     
o A patient failing to meet all protocol requirements may not be registered.  Patients 
must be registered prior to initiation of protocol therapy.  
o Once a patient is eligible, all the pre-study requirements have been fulfilled, and the 
informed consent obtained, the research nurse or the data manager (study 
coordinator) at the participating center will inform the Data Coordinating Center 
(626-256-4673, ext 63968; pager 626-423-6486) and FAX (fax number 626-301-8422) a 
copy of the signed informed consent, patients’ Bill of Rights, signed HIPPA consent, 
completed eligibility checklist and corresponding source documentation confirming 
eligibility (including pathology reports, lab reports, x-ray reports, etc.). 
 
The City of Hope Data Coordinating Center will: 
 
o Review all materials received to ensure the patient is eligible.  
o Ensure the consent form is valid and is signed correctly by all parties.  If additional 
information is needed or should there be any questions, the Data Coordinating 
Center will immediately contact the participating institution and registration will not 
occur until all issues are resolved.  No exceptions will be granted.   
o The patient will be registered centrally at City of Hope.    
o Confirmation of Registration will be emailed/faxed to the participating institution 
noting study number as well as assigning the dose (if applicable) within 24 hours via 
fax or email.    
o The Data Coordinating Center will call the research nurse or data manager (study 
coordinator) at the participating site and verbally confirm registration. 
o If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be cancelled.  The Data Coordinating Center should be 
notified of cancellations as soon as possible. 
 
3.4  Procedures for On-Study and Treatment Deviations   
 
Any amendments to the study protocol need to be approved by the IRB at the study sponsor site, City of 
Hope, and then at the participating center.  All deviations or single subject exceptions to the study 
protocol must be reported to the primary IRB of the participating site, and to Dr. Matthew Mei, the study 
PI at the sponsor institution. 


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  3.5  Study Treatments 
3.5.1  Clinical Trial Materials 
Bortezomib for Injection is a sterile lyophilized powder for reconstitution and is supplied in vials 
containing bortezomib and mannitol at a 1:10 ratio.  For example, vials containing 3.5 mg of bortezomib 
contain 35 mg of mannitol.   
Rituximab antibody will be provided in 100 mg (10ml) and 500 mg (50 ml) vials at a concentration of 
10.0 mg of protein per mL. 
  3.5.2  Preparation, Handling, and Storage of Drugs 
 
Bortezomib 
Vials containing lyophilized bortezomib 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. 
Bortezomib is cytotoxic.  As with all cytotoxic drugs, caution is required when preparing and handling 
bortezomib 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. 
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 Chloride Injection USP, so that the reconstituted 
solution contains bortezomib at a concentration of 2.5 mg/mL for subcutaneous administration.  
 
Intravenous administration  
Drug is available in sterile, single use vials containing 3.5 mg of bortezomib. x  Each vial of bortezomib 
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, Sodium Chloride Injection USP, so that the 
reconstituted solution contains bortezomib at a concentration of 1 mg/mL for intravenous administration.  


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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 bortezomib 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. 
 
Rituximab is stored at 2-8. Reconstituted antibody is stable for 24 hours upon refrigeration followed by 12 
hours at room temperature.  It needs to be diluted with normal saline to a concentration of 1-4 mg/ml.  
Shaking can cause aggregation and precipitation of the antibody and should be avoided.  The route of 
administration is intravenous.  Rituximab is commercially available in 10 mL (100mg) and 50 mL (500 
mg) single-use vials at a concentration of 10mg/ml.  Use of rituximab is considered standard of care for 
this indication, and will not be provided by Millennium.  Do not mix or dilute rituximab with other drugs.  
No incompatibilities between rituximab and polyvinylchloride or polyethylene bags have been observed.   
 
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. 
 
3.5.3 Drug administration and dosage schedule  
Table 3.5. Treatment Schema 
 
Pre-
Study 
Day 1 
Day 8 
Day 
15 
Day 
22 
 
bortezomib 
 
X 
X 
X 
X 
Repeat 
every 3 
month x 
8 cycles 
rituximab 
 
X 
X 
X 
X 
Repeat 
every 6 
month x 
4 cycles 
 
Bortezomib will be administered on D1, 8, 15, and 22 every 3 month for a total of 8 cycles.  Bortezomib 
dosing will be 1.3 mg/m2 


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Rituximab will be administered on D1, 8, 15, 22 every 6 month for a total of 4 cycles. Rituximab dosing 
will be 375 mg/m2 
 
Bortezomib Administration 
 
Intravenous and subcutaneous route of administration have different reconstituted concentration. 
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 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 bortezomib, a local reaction was reported in 6% of patients as an adverse event, 
mostly redness. 
 
 
INTRAVENOUS 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 3.5 mL of normal (0.9%) saline, Sodium Chloride Injection USP, so that the reconstituted 
solution contains bortezomib at a concentration of 1 mg/mL for intravenous administration.  
 
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.   


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The pharmacist will prepare the drug under aseptic conditions.  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 on Day 1 of 
each cycle; the dose administered should remain the same throughout each cycle but should be 
recalculated at the start of the next cycle.  If a patient experiences a notable change in weight (e.g., loss or 
gain of 8 lbs or 3.6 kg) within a cycle, as determined by an unscheduled weight assessment, then the 
patient’s dose should be recalculated at that time. 
 
The appropriate amount of bortezomib will be drawn from the injection vial and administered as an IV  
push over 3 to 5 seconds.  Vials are for single use administration.  There must be at least 72 hours 
between each dose of bortezomib. 
 
Rituximub administration  
Rituximab will be administered only to eligible patients under the supervision of the investigator or 
identified sub-investigators.  Patients may be treated on an out-patient basis, if possible.  The pharmacist 
will prepare the drug under aseptic conditions.  The amount (in mg) of the 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 on Day 1 of each cycle; the dose 
administered should remain the same throughout each cycle but should be recalculated at the start of the 
next cycle.  If a patient experiences a notable change in weight (e.g., loss or gain of > 8 lbs or 3.6 kg) 
within a cycle, as determined by an unscheduled weight assessment, then the patient’s dose should be 
recalculated at that time.   
 
 3.5.4Dose Modification and Delay 
Dose escalation will not be allowed in any patient. 
 
There will not be any dose modification for rituximab or dose delay.   
 
Table 3.2 Dosing Level Schema 
 
Bortezomib 
rituximab 
Level 1 
1.3 mg/m2 
375 mg/m2 
Level -1 
1.0 mg/m2 
375 mg/m2 
Level -2 
0.7 mg/m2 
375 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 4.0.  
 
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: 


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If the patient experiences febrile neutropenia, a Grade 4 hematologic toxicity (including a platelet count 
<50  109/L) or any Grade 3 non-hematologic toxicity considered by the investigator to be related to 
bortezomib, then drug is to be held. 
 
For non-hematologic toxicities, bortezomib is to be held for up to 2 weeks until the toxicity returns to 
Grade 1 or better. For infection toxicities, bortezomib can be held up for 3 weeks until toxicity returns to 
grade 2 or better.   
 
For hematologic toxicities, bortezomib is to be held for up to 2 weeks until the patient has a hemoglobin 
value of 9 , platelet value of 75,000 , and absolute neutrophil value of >1000.  Growth factors, packed red 
blood cell and plt transfusions may be given as needed.   
Dose interruption or study discontinuation is not required for lymphopenia of any grade.   
 
If, after bortezomib has been held, the toxicity does not resolve, or improve to grade 1, as defined above, 
then drug must be discontinued. For infection toxicities, if after the bortezomib has been held for 3 weeks, 
and the toxicity does not resolve or improve to grade 2, then the drug must be discontinued.   
 
If the toxicity resolves, as defined above, and bortezomib is to be restarted, the dose must be reduced by 
approximately 25% for this cycle as follows: 
 
1. 
If the patient was receiving 1.3 mg/m2, reduce the dose to 1.0 mg/m2. 
2. 
If the patient was receiving 1.0 mg/m2, reduce the dose to 0.7 mg/m2. 
3. 
If the patient was receiving 0.7 mg/m2, discontinue drug 
4. 
If the patient received a reduced dose of bortezomib without return of toxicities, then the patient 
can receive the prior dose of drug without the 25% dose reduction at the next cycle. 
5. 
No dose adjustment is necessary for rituximab.   
6. 
Premedication such as Benadryl, Tylenol, and hydrocortisone can be given to treat and prevent 
infusion related reactions from rituximab. 
 
Patients who experience bortezomib -related neuropathic pain and/or peripheral sensory neuropathy are to 
be managed as presented in Table 3.1 Management of Patients with bortezomib -Related Neuropathic 
Pain and/or Peripheral Sensory Neuropathy. Once the dose is reduced for peripheral neuropathy, the 
dose may not be re-escalated. 
  
 


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Table 3-4    
Management of Patients with bortezomib Related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy (Mandatory With Adjustments as 
Necessary)  
Recommended Dose Modification for bortezomib 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 bortezomib to 1.0 mg/m2 
Grade 2 with pain or Grade 3 (interfering with  
activities of daily living)  
Withhold* bortezomib therapy until  
toxicity resolves.  
When toxicity resolves reinitiate with  
a reduced dose of bortezomib at 0.7mg.m2 and change  
treatment schedule to once per week.*  
Grade 4 (Sensory neuropathy which is disabling or motor 
neuropathy that is life threatening or leads to paralysis)  
Discontinue bortezomib  
Grading based on NCI Common Terminology Criteria CTCAE v4.0    
NCI Common Terminology Criteria website - http://ctep.info.nih.gov/reporting/ctc.html  
ADL = activities of daily living 
*Key: 
Reduce by one dose level: 
bortezomib dose reduction from 1.3 to 1.0, or 1.0 to 0.7 mg/m2/dose.  
Hold:   
 
 
Interrupt bortezomib for up to 2 weeks until the toxicity returns to Grade 1 or better. 
Schedule change:                    There is no schedule changes 
 
The neurotoxicity-directed questionnaire (see section 8.7) 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. 
 
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. 
 
 


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  3.5.5 Blinding, Packaging, and Labeling 
Bortezomib will be supplied in vials as open-label stock.  Both the box label and vial label will fulfill all 
requirements specified by governing regulations.   
Rituximab will be supplied in vials as open-label stock.  Both the box label and vial label will fulfill all 
requirements specified by governing regulations.   
3.5.6 Concomitant Treatment 
Required Concurrent Therapy 
The following medications/supportive therapies can be used during study participation, as applicable: 
G-CSF 
Platelets transfusions 
Packed red blood cell transfusions 
Antibiotic therapy 
Prednisone 
Investigators should consider using antiviral prophylaxis in subjects being treated with bortezomib 
 
Prohibited Concurrent Therapy 
 
Any investigational agent other than bortezomib  
  3.5.7 
Treatment Compliance 
All drugs 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 milligram. Any discrepancy between the 
calculated dose and dose administered and the reason for the discrepancy must be recorded in the source 
documents. 
 
 3.6 Duration of Treatment and Patient Participation 
In the absence of treatment delays dues to adverse events, treatment should continue for 4 cycle of 
rituximab and 8 cycles of bortezomib. 
Screening period is between D 60 to D 180 after HSCT.  Patients will be on treatment for 2 years 
durations and be followed for 3 additional years for a total of 5 year follow up.   
Termination of Treatment and/or Study Participation 


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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 
Occurrence of an unacceptable adverse event 
A treatment cycle delay or bortezomib interruption of >2 weeks or missing three of four 
bortezomib                                                                                                                                                      
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, all study procedures outlined for the End of Study visit should be completed.  
The primary reason for a patient’s withdrawal from the study is to be recorded in the source documents. 
 
3.7 Efficacy, Pharmacodynamic/Pharmacogenomic/Correlative studies, and Safety Measurements 
 
3.7.1 Efficacy Measurements 
Patients will be undergoing CT/PET scans or full body CT scans every 6 months for assessment of 
disease.  The imaging needs to be obtained within 1-2 weeks prior to dosing of each subsequent 
cycle of bortezomib or Rituximab.  After 2 years of treatment, CT/PET or full body CT scans can 
be spaced to once a year until a follow up of 5 years is reached.   
Patients will have bone marrow biopsy done as baseline of study.  Bone marrow biopsy will be 
performed every 6 month during 1st  two years of study then yearly.  It will also be performed at 
the time of relapse or suspected relapse.   
Disease response will be assessed and defined by the revised Cheson Criteria (Cheson 2007) 
 
Complete response (CR): 
Complete disappearance of all detectable clinical and radiographic evidence of disease and 
disappearance of all disease related symptoms if present before therapy. 


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All lymph nodes and masses must regress to normal size (< 1.5 cm in greatest transverse 
diameter if > 1.5 cm prior to treatment) or become PET negative.  
If bone marrow was involved by lymphoma, it must be cleared as documented by biopsy at 
the same location.   
 
Progressive disease (PD): Appearance of any new lesion during or at the end of therapy. 
 
Survival: defined as the time form registration to time of death due to any cause.  If a patient is not 
known to have died, survival time is censored at the time of last follow-up.  Patients will be 
followed till death. 
 
Progression free survival:  Defined as the time from registration to the first observation of disease 
progression or death due to any cause.  If a patient has not progressed or died, progression-free 
survival is censored at the time of last follow-up.   
 
3.7.2 Pharmacokinetic/Pharmacodynamic/Pharmacogenomic/Correlative Studies--Correlative Studies 
will be done at City of Hope only.    
 
Patients will have bone marrow biopsy done as baseline of study.  Bone marrow biopsy will be 
performed every 6 months during 1st two years of study then yearly.  It will also be performed at 
the time of relapse or suspected relapse.   
Patients will have peripheral blood samples done at baseline, and every 3 months during 1st and 2nd 
year of study and then yearly.  It will also be performed at the time of relapse or suspected relapse.   
Paraffin block from the representative diagnostic section or 12 unstained paraffin slides will be 
obtained from diagnostic material and the time of relapse. These can be from fresh or fixed tissue. 
We will examine CCND1 expression, CCND1 mRNA expression, and its isomer expression in 
peripheral blood, bone marrow samples, and lymph nodes samples (from diagnostic sample).  We 
will also examine proliferation markers such as Ki-67 and others by immunohistochemistry.  All 
samples will be analyzed at Beckman Research Institute under Dr. John Rossi laboratory. 
There are two sets of biomarkers that will be evaluated in this study.  The 1st set of biomarkers to 
be tested is Ki-67 expression and CCND1 truncated isomer expression.  This biomarker would be 
examined in primary tumor tissue, including lymph nodes (from diagnostic sample) and bone 
marrow and peripheral blood specimens.  Ki-67 expression and CCND1 truncated isomer has been 
shown in previous study to predict for prognosis in a retrospective pattern.  However, it has not 
been evaluated in a prospective trial.  We will be looking to see if maintenance treatment with 


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bortezomib + rituximab after AHCT would be able to overcome the poor prognosis predicted by 
high Ki-67 expression (30% or higher) or the presence of the truncated CCND1 isomer. 
The second set of biomarkers to be evaluated is CCND1 mRNA expression in bone marrow and 
peripheral blood.  Although MCL is the only lymphoma that expresses CCND1, normal tissues 
such as GI tract can also produce CCND1 mRNA.  It has not been used as an early marker for 
relapse due to background noise from normal tissue.  In this study, we hope to evaluate the 
expression of CCND1 mRNA in the bone marrow and peripheral blood longitutionally from serial 
measurements.  We hope to correlate an increase in CCND1 mRNA from baseline with relapse.   
 
Blood sample collection and storage for DNA and RNA analysis: 
Prior to drug administration on Day 1 of each cycle then every 6 months through year two 
and yearly thereafter to five years. 
25 ml of blood will be obtained in EDTA (lavender-topped) tubes to measure CCND1 
mRNA.  The blood for isolation of cells may be drawn from a central line or peripherally. 
Samples will be stored in the Beckman Research Institute Rossi laboratory.  Following 
completion of this study, samples will remain in storage.  If, at any time, a patient 
withdraws from the study and does not wish for their existing samples to be utilized, the 
individual must provide a written request.  Following receipt of this request, the samples 
will be destroyed and reported as such to the IRB.  Existing data from samples already 
distributed or analyzed will be retained and may be published without identification of 
individual patients. 
 
Any new use of these samples will require prospective IRB review and approval; any loss or 
destruction of samples and the planned disposition of samples after the protocol is terminated will 
be reported to the IRB. 
 
Bone Marrow Aspirate sample collection and storage for DNA/RNA analysis. 
Each time a bone marrow aspiration is obtained for clinical management of the patient, additional 
aspirate will be obtained and transferred into a BD vacutainer CPT tube with sodium heparin. 
 
  3.7.3  Safety Measurements 
 
Safety assessments will consist of monitoring and recording all adverse events, including serious 
adverse events, the regular monitoring of hematology, serum chemistry, routine monitoring of vital 


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signs (heart rate, blood pressure, and body temperature) and physical condition.  Toxicity will be 
assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, Version 4.0. 


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4  STATISTICAL PROCEDURES 
  4.1  Sample Size Estimation 
The aim of this study is to examine the anti-tumor activity/efficacy of this maintenance regimen in 
eligible patients. The City of Hope historical rate of DFS is 60%, which is a consistent with what is 
reported in literature.  This is an efficacy study.  We expect a disease-free survival rate (DFS) (primary 
endpoint) to improve by 20% with this maintenance therapy.  To achieve a DFS of 80% at two years, we 
need a sample size of 36 evaluable patients. (alpha=0.05, 1-beta=0.80).  With adequate follow-up time, 
the endpoints of DFS, overall survival (OS), and time to treatment failure will be assessed by Kaplan-
Meier survival analysis and 95% confidence intervals will be calculated using Greenwood’s formula.  
Based on the current referral patterns to the City of Hope, it is expected that approximately 5 patients per 
year will be enrolled in this study; approximately five years of accrual will be required.  
  
While early stopping rules have been incorporated into the study for excessive toxicity; there will be no 
interim analysis for efficacy. Toxicities will be recorded using the NCI CTCAE 4.0 Scale. The table 
below will be consulted as relevant toxicities are encountered. 
 
Early Stopping Criteria: For each adverse outcome, stop if the cumulative number of patients reaches or 
exceeds the following limits: 
 
 
Table of Early Stopping Criteria 
 
 
 
 
 
# of patients treated 
 
 
# of patients expired due 
to treatment related 
causes that would stop 
the study*  
 
 
# of patients with ≥grade 
3 toxicities that would 
require an evaluation for 
safety** and *** 
Probability that the early stopping 
rule will be invoked given a 
failure rate of: 
10% 
15% 
20% 
12 
3 
3 
0.11 
0.26 
0.45 
18 
5 
5 
0.12 
0.27 
0.47 
24 
6 
6 
0.12 
0.31 
0.53 
30 
8 
8 
0.13 
0.31 
0.53 
36 
9 
9 
0.13 
0.32 
0.55 
* Note:  The stopping rules are not statistically based; expected treatment related mortality should not to exceed 25%. 
** Note: For hematologic toxicities: Any grade 4 neutropenia associated with fever or infection and lasting beyond three weeks, or grade 4 neutropenia lasting 
for more than 28 days per CTCAE 4.0 toxicity criteria should be counted toward the early stopping rule. 
 
***Note: For infection toxicities, only grade 3 that does not resolve within 3 weeks or any grade 4 events would require an evaluation for safety.  As these 
patients are post AHCT and start onto study within a year post AHCT, their immune system has not recovered to normal and grade 3 infection events can occur 
even without maintenance treatment.   
 
Any patient who receives treatment will be evaluable for toxicity. Each patient will be assessed 
periodically according to the treatment schedule for the development of any toxicity. The toxicity rule for 
safety will be assessed as each patient reaches day +90 post initiation of bortezomib. If more than the 
specified number of patients (noted in the table above) have significant treatment related toxicities, then 
the safety of the study will be evaluated. Based on this evaluation the study will either be amended to 
reduce the dose/adjust schedule or will be closed. 
 


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4.2 Randomization and Stratification 
Randomization/stratification will not be used in this study 
4.3 Populations for Analysis 
MCL lymphoma patients s/p autologous hematopoietic stem cell transplantation 
4.4 Statistical Methods 
The toxicities observed will be summarized in terms of type (e.g. organ affected or ANC) severity (by 
NCI CTCAE v4.0 and nadir or maximum values for the laboratory measures), date of onset, duration, 
reversibility, and attribution. Tables will be created to summarize these toxicities and side effects. 
Baseline information (e.g., the extent of prior therapy) and demographic information will be presented for 
all study patients.  
 
In accordance with the primary study objectives, we will perform descriptive statistical analyses on these 
data after the study is complete. With adequate follow-up time, the endpoints of DFS, overall survival 
(OS), and time to treatment failure will be assessed by Kaplan-Meier survival analysis and 95% 
confidence intervals will be calculated using Greenwood’s formula. DFS will be defined as the time from 
first treatment day until objective or symptomatic relapse or death as a result of lymphoma or acute 
toxicity of treatment. OS will be defined as the time from first treatment day until death.   
4.5  Protocol Deviations 
  4.5.1 Deviation Policy 
Brief interruptions and delays may occasionally be required due to travel delays, airport closure, 
inclement weather, family responsibilities, security alerts, government holidays, etc.  This can also extend 
to complications of disease or unrelated medical illnesses not related to disease progression.  These delays 
of up to three days will not be considered protocol deviations. 
 
Planned deviations may be permitted in accordance with the COH policy on “Clinical Research Protocol 
Planned Deviations and Single Subject Exception.”  These planned deviations, considered Single Subject 
Exceptions, are considered an Amendment to the Protocol.  In addition, if contractually obligated, the 
sponsor must also approve any planned deviations. 
  4.5.2  Reporting of Unplanned Deviations 
All unplanned deviations will be reported to the COH DSMB who will forward to the IRB following 
review. 
  4.5.3  Resolving Disputes 
If there is a dispute among the persons involved in the provision of research treatment, in regard to 
whether a treatment deviates from the protocol, resolution will be resolved in accordance with the Clinical 
Research Protocol Planned Deviations and Single Subject Exceptions policy. 


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4.6  Results Reporting 
The COH, as sponsor of IND #112273, will submit reports annually to the FDA within 60 days of the 
anniversary date that the IND went into effect in accordance with 21 CFR 312.33. 
 
 
5  HUMAN SUBJECTS PROTECTION 
  5.1 Data and Safety Monitoring 
a) Definition of Risk Level 
This is a Risk Level 4 study, as defined in the “City of Hope Data and Safety Monitoring 
Plan”, http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx involving COH as IND 
holder and is a phase II study of weekly maintenance using bortezomib and rituximab for 
mantle cell lymphoma.   
b) Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) consisting of the PI, Collaborating 
Investigator, CRA/protocol nurse, and statistician is responsible for monitoring the 
data and safety of this study, including implementation of the stopping rules for 
safety and efficacy. 
Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting Requirement 
RL 1, RL2, and  
Expanded Access Studies 
No reports required 
3 
I 
Every 3 months from activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from activation date, as 
indicated in MIDAS 
Data and safety will be reported to the COH DSMC using the PMT report and submitted 
quarterly from the anniversary date of activation .  Protocol specific data collection will 
include the following items: hematological response, toxicities of treatment, and survival.  
The planned endpoints is two years DFS.     


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5.2    Definitions 
 
Adverse event (AE) - An adverse event is any untoward medical experience or change of an 
existing condition that occurs during or after treatment, whether or not it is considered to be 
related to the protocol intervention.  
 
Unexpected Adverse Event [21 CFR 312.32 (a)] – An adverse event is unexpected if it is not 
listed in the investigator’s brochure and/or package insert; is not listed at the specificity or 
severity that has been observed; is not consistent with the risk information described in the 
protocol and/or consent; is not an expected natural progression of any underlying disease, 
disorder, condition, or predisposed risk factor of the research participant experiencing the 
adverse event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event 
OR is an expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse event. 
 
Serious Adverse Event (SAE) [21 CFR 312.32] - defined as any expected or unexpected adverse event 
that results in any of the following outcomes: 
 Death 
 Is life-threatening experiences (places the subject at immediate risk of death from the 
event as it occurred) 
 Unplanned hospitalization equal or greater than 24 hours)) or prolongation of existing 
hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Secondary malignancy 
 Any other adverse event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of 
the outcomes listed above (examples of such events include allergic bronchospasm 
requiring intensive treatment in the emergency room or at home, blood dyscrasias of 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse). 
 
Unanticipated problem (UP) - Any incident, experience or outcome that meets all three of the 
following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 
protocol, informed consent document or Investigator Brochure (IB); and b) the 
characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by 
the drugs, devices or procedures involved in the research); AND 


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Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than previously known or recognized. 
5.3   Reporting of Unanticipated Problems and Adverse Events 
 
Unanticipated Problems - Most unanticipated problems must be reported to the COH DSMC 
and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/policy/Policies%20and%20Procedures/REVIEWING_AND_REPORTING_
UNANTICIPATED_PROBLEMS.pdf.  Any unanticipated problem that occurs during the study 
conduct will be reported to the DSMC and IRB by submitting electronically in iRIS 
(http://iris.coh.org). 
 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed by the 
physician, nurse, or reported by the patient, will be reported according to definitions and 
guidelines at 
http://www.coh.org/policy/Policies%20and%20Procedures/REVIEWING_AND_REPORT
ING_UNANTICIPATED_PROBLEMS.pdf and Table 2 below.  Those SAEs that require 
expedited reporting will be submitted electronically in iRIS (http://iris.coh.org). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that do not 
meet the criteria of serious OR are not unanticipated problems will be reported only in the 
continuation reports and PMT reports (see Table 2 below). 
 
 
 
DSMC Risk Level 3 and Risk Level 4 Protocol Reporting Timelines 
 
Required Reporting Timeframe to the DSMC 
Attribution 
Unexpected 
Expected 
Death while on active treatment or within 30 days of last day of treatment 
Possibly, Probably, Definitely 
5 calendar days 
Unlikely, Unrelated 
Death after 30 days of last active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
Within 30 days of last active treatment/therapy 
  
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
 
Grades 1 and 2 AND resulting in “hospitalization” 


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Required Reporting Timeframe to the DSMC 
Attribution 
Unexpected 
Expected 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 
After 30 days of last active treatment/therapy 
 
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
 
Grades 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, Definitely 
10 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 


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DSMC Risk Level 1 and Risk Level 2 Protocol Reporting Timelines 
Required Reporting Timeframe to DSMC 
Attribution 
Unexpected 
Expected 
  
Death while on active treatment or within 30 days of last day 
of treatment 
Possibly, Probably, Definitely 
5 calendar days 
5 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of “serious” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 1 and 2 AND resulting in “hospitalization” 
Possibly, Probably, Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
No reporting required 
No reporting required 
 
 
 
COH IRB Adverse Event Reporting Timelines  
 
Required Reporting Timeframe to COH IRB  
Attribution 
Unexpected 
Expected 
 
Death while on active treatment/therapy or within 30 days 
of the last day of active treatment/therapy 
Possibly, Probably, Definitely 
5 calendar days1 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 
Possibly, Probably, Definitely 
5 calendar days1 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 
Possibly, Probably, Definitely 
5 calendar days1 
Annual2 
Unlikely, Unrelated 
Annual2 
Annual2 
1 These events must be reported in the time frame if they meet the definition of an unanticipated problem. 
2 For studies that are not first in human, Phase I and first in pediatric trials, only grades 3-5 must be reported at annual review.  
ADDITIONAL REPORTING REQUIREMENTS  
 
SAEs meeting the requirements for expedited reporting to the FDA, as defined in 21 CFR 312.32, will be 


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reported as an IND safety report using the MedWatch Form FDA 3500A for Mandatory Reporting which 
can found at: http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
The PI or designee will be responsible for contacting the Office of IND Development and Regulatory 
Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA.  OIDRA will assist 
the PI with the preparation of the report and submit the report to the FDA in accordance with the 
following: 
 
any unexpected fatal or life threatening adverse experience associated with use of the drug must be 
reported to the FDA no later than 7 calendar days after initial receipt of the information [21 CFR 
312.32(c)(2)] 
 
 
any adverse experience associated with use of the drug that is both serious and unexpected must be 
submitted no later than 15 calendar days after initial receipt of the information [21 CFR 
312.32(c)(1)] 
 
 
any follow-up information to a study report shall be reported as soon as the relevant information 
becomes available. [21 CFR 312.32(d)(3)] 
 
In addition to reporting to COH DSMC and IRB, SAEs must be reported to Millennium 
Pharmacovigilance.  The procedures are as follows: 
 
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) from first dose of 
bortezomib up to and including 30 days after administration of the last dose of bortezomib.  When 
possible, signs and symptoms indicating a common underlying pathology should be noted as one 
comprehensive event.  Any SAE that occurs at any time after completion of bortezomib treatment or after 
the designated follow-up period that the investigator and/or sub-investigator considers to be related to any 
study drug must be reported to the 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). 
This is an investigator-initiated study.  The principal investigator (who may also sometimes be referred to 
as the sponsor-investigator), is conducting the study and acting as the sponsor. Therefore, the legal/ethical 
obligations of the principal investigator include both those of a sponsor and those of an investigator.  
Sponsor-investigator must report all SAEs, regardless of expectedness or relationship with any study 
drug, to Millennium Pharmacovigilance (or designee) as soon as possible, but no later than 5 calendar 
days of the sponsor-investigator’s observation or awareness of the event.  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 


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foregoing reporting obligations to Millennium Pharmacovigilance, unless otherwise agreed between the 
sponsor-investigator and sub investigator(s).  Millennium Pharmacovigilance (or designee) may request 
follow-up information to a reported SAE, which the sponsor-investigator will be responsible for providing 
to Millennium Pharmacovigilance (or designee). 
Millennium will provide a sample SAE Report Form representative of the information Millennium 
Pharmacovigilance may request in follow-up (see Appendix 9.7).   
The SAE report must include event term(s), serious criteria, and the investigator’s or sub-investigator’s 
determination of both the intensity of the event(s) and the relationship of the event(s) to study drug 
administration. 
Intensity for each SAE, including any lab abnormality, 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.  
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 or study drug(s), including, but 
not limited to, telephone conversation logs, as soon as possible but no later than 5 calendar days of such 
communication. 
 
Millennium Pharmacovigilance 
SAE and Pregnancy Reporting Contact Information: 
North America 
PPD, Inc. 
Safety and Medical Management, US 
Fax:  +1 888-488-9697 
Hotline number (available 24/7):  1-800-201-8725 
 
5.3     Millennium Definitions: 
 
Adverse Event - 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. 
 
 
Serious Adverse Event –  
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 an existing hospitalization. 
 Results in persistent or significant disability or incapacity.  (Disability is defined as a substantial 
disruption of a person’s 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 one of the outcomes listed above, or involves suspected transmission via a medicinal 
product of an infectious agent.    
o 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. 
o With respect to the suspected transmission via a medicinal product of an infectious agent; 
any organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible 
Spongiform Encephalopathy), whether pathogenic or non-pathogenic, is considered an 
infectious agent.   
Clarification should be made between the terms serious and severe because they ARE NOT the same.  
The term severe is often used to describe the intensity (severity) of a specific event (as in mild, moderate, 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 


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significance (such as a severe 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 functioning.  A severe AE does not necessarily need to be considered serious.  
For example, persistent nausea of several hours duration may be considered severe nausea but may not be 
considered an SAE.  On the other hand, a stroke resulting in only a minor degree of disability may be 
considered mild but would be defined as an SAE based on the above noted criteria.  Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations. 
 
Safety Reporting Requirements and Timelines – Participating Sites 
The guideline is to provide a procedure for accurate and timely reporting of unanticipated problems 
and/or adverse events meeting reporting criteria as defined in Section 5.2 of this protocol for 
participating sites.  The participating site, including the participating Principal Investigator and/or 
study coordinators are responsible for reporting all unanticipated problems and/or adverse events 
immediately (within 24 hours after learning of the event) to their local IRB, the Principal 
Investigator at City of Hope, and the Data Coordinating Center at COH. 
The participating Principal Investigator must report each unanticipated problem and/or adverse event, 
regardless of attribution, to the City of Hope Principal Investigator, Dr. Matthew Mei and to the 
Data Coordinating Center at City of Hope within 24 hours of learning of the occurrence. In the 
event that the participating site Principal Investigator and/or staff does not become aware of the 
unanticipated problem and/or adverse event immediately (e.g., participant sought treatment 
elsewhere), the participating site is to report the event within 24 hours after learning of it and 
document the time of his or her first awareness of the unanticipated problem and/or adverse 
event.    
Report to City of Hope all unanticipated problems and/or serious adverse events (meeting criteria as 
defined in Section 5.2) by telephone (to Dr. Matthew Mei and the DCC) and send via scan/email 
and fax a copy of the following forms: 
 Notification of Unanticipated Problem/Serious Adverse Event Form (located at end of the 
protocol).  This is a coversheet for all reports submitted as required. 
 Participating sites internal serious adverse event form.  This is the form/report that participating 
sites submit to their IRB of record. 
 Millennium Serious Adverse Event Form (located at end of the protocol) 
SAE Notification Contact Numbers: 
 
 
 
Dr. Matthew Mei 
 
Phone: 626-256-4673x82405 Fax:  626-301-8116  
 
Data Coordinating Center Phone:  626-256-4673x63968 
Email:  dcc@coh.org 
 
 
 
 
 
   (Please use #secure# in the subject line) 


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The Data Coordinating Center at City of Hope, after review of all information and documents provided 
by the participating site, and in collaboration with the City of Hope Principal Investigator, will 
submit to the appropriate committees/company as follows: 
 City of Hope IRB and DSMC and the Office of IND Development and 
Regulatory Affairs (as applicable) using the City of Hope’s electronic 
submission system (IRIS) 
 Millennium Pharmacovigilance, using the Millennium Serious Adverse Event 
Form 
Any supporting documentation to the reports (i.e., laboratory, pathology, progress notes, discharge 
summary, autopsy, etc.) explaining the adverse event should also be submitted to the Data 
Coordinating Center at City of Hope.  The Data Coordinating Center will then submit to our 
COH committees (using IRIS) as well as submit to Millennium in a timely manner. 
5.4  Participation of Children 
Participants under the age of 18 will be excluded from study because no dosing or adverse event data 
are currently available for the use of bortezomib + rituximab in participants < 18 years of age. 
5.5  Evaluation of benefits and Risks/Discomforts 
There may or may not be any clinical benefit to a patient from participation in this trial.  Their 
participation will benefit future cancer patients.  Potential risks include the possible occurrences of 
any of a range of side effects that are listed in the consent document.  The procedure for protecting 
against or minimizing risks will be to medically evaluate patients as described in protocol Section 6.3. 
If patients suffer any physical injury as a result of participation in this study, immediate medical 
treatment is available.  Although no compensation is available, any injury will be fully evaluated and 
treated in keeping with the benefits or care to which participants are entitled under applicable 
regulations. 
 
5.6Procedures 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 must permanently discontinue study drug(s).  All pregnancies 
and suspected pregnancies must be reported to Millennium Pharmacovigilance (or designee; see Section 
6.10 for contact information) immediately.  The pregnancy must be followed for the final pregnancy 
outcome (ie, delivery, still birth, miscarriage) and Millennium Pharmacovigilance will request this 
information from the investigator. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in this 
study, this must be reported to Millennium Pharmacovigilance (or designee) immediately (see Section 
6.10 for contact information).  Every effort should be made to follow the pregnancy for the final 
pregnancy outcome. 


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6  ADMINISTRATIVE REQUIREMENTS 
6.1  Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation (ICH) for 
Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The investigator will be 
thoroughly familiar with the appropriate use of the drug as described in the protocol and Investigator’s 
Brochure.  Essential clinical documents will be maintained to demonstrate the validity of the study and 
the integrity of the data collected.  Master files should be established at the beginning of the study, 
maintained for the duration of the study and retained according to the appropriate regulations.   
6.2  Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki 
(see section 8.5).  The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety and well-being of the patients.  The study will only be conducted at sites where IRB/IEC 
approval has been obtained.  The protocol, Investigator’s Brochure, informed consent, advertisements (if 
applicable), written information given to the patients (including diary cards), safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB/IEC by the 
investigator.  Millennium requests that informed consent documents be reviewed by Millennium or 
designee prior to IRB/IEC submission.   
6.3  Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either the patient 
or his/her guardian or legal representative prior to study participation.  The method of obtaining and 
documenting the informed consent and the contents of the consent will comply with ICH-GCP and all 
applicable regulatory requirement(s). 
6.4  Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, study reports 
and communications will identify the patient by initials and the assigned patient number.  The investigator 
will grant monitor(s) and auditor(s) from Millennium or its designees and regulatory authority(ies) access 
to the patient’s original medical records for verification of data gathered on the data capture records and 
to audit the data collection process.  The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations. 
6.5  Protocol Compliance 
The investigator will conduct the study in compliance with the protocol given approval/favorable opinion 
by the IRB/IEC and the appropriate regulatory authority(ies).  Changes to the protocol will require 
approval from Millennium and written IRB/IEC approval/favorable opinion prior to implementation, 
except when the modification is needed to eliminate an immediate hazard(s) to patients.  The IRB/IEC 
may provide, if applicable regulatory authority(ies) permit, expedited review and approval/favorable 
opinion for minor change(s) in ongoing studies that have the approval /favorable opinion of the IRB/IEC.  


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The investigator will submit all protocol modifications to Millennium and the regulatory authority(ies) in 
accordance with the governing regulations.  
Any departures from the protocol must be fully documented in the source documents.   
6.6  On-site Audits 
Regulatory authorities, the IEC/IRB and/or Millennium’s clinical quality assurance group may request 
access to all source documents, data capture records, and other study documentation for on-site audit or 
inspection.  Direct access to these documents must be guaranteed by the investigator, who must provide 
support at all times for these activities. 
6.7  Drug Accountability 
Accountability for the drug at all study sites is the responsibility of the principal investigator.  The 
investigator will ensure that the drug is used only in accordance with this protocol.  Drug accountability 
records indicating the drug’s delivery date to the site (if applicable), inventory at the site (if applicable), 
use by each patient, and return to Millennium or disposal of the drug (if applicable and if approved by 
Millennium) will be maintained by the clinical site.  Accountability records will include dates, quantities, 
lot numbers, expiration dates (if applicable), and patient numbers.   
 
All material containing bortezomib will be treated and disposed of as hazardous waste in accordance with 
governing regulations. 
6.8  Premature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator or Millennium, there is 
sufficient reasonable cause.  Written notification documenting the reason for study termination will be 
provided to the investigator or Millennium by the terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
1. 
Determination of unexpected, significant, or unacceptable risk to patients 
2. 
Failure to enter patients at an acceptable rate 
3. 
Insufficient adherence to protocol requirements 
4. 
Insufficient complete and/or evaluable data 
5. 
Plans to modify, suspend or discontinue the development of the drug 
Should the study be closed prematurely, all study materials must be returned to Millennium. 
6.9  Record Retention 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).   
6.10  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 


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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. 
 
For Product Complaints or Medication Errors,  
call MedComm Solutions at 
1-510-740-1273 (international number) 
1-866-835-2233 (for US sites)  
 
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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Moreau P, Coiteux V, Hulin C, et al.  Prospective comparision of subcutaneous versus intravenous 
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