Conditions: Recurrent Classic Hodgkin Lymphoma Refractory Classic Hodgkin Lymphoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
This phase II trial studies how well combination chemotherapy with or without bortezomib works in treating patients with classical Hodgkin lymphoma that has come back or does not respond to prior treatment. Drugs used in chemotherapy, such as ifosfamide, carboplatin, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bortezomib is designed to block a protein that plays a role in cell function and growth. Bortezomib may cause cancer cells to die. It is not yet known if combination chemotherapy with or without bortezomib may work better in treating patients with classical Hodgkin lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the objective response rate (ORR), partial remissions (PR), and complete remissions (CR) after 3 cycles of bortezomib plus ifosfamide, carboplatin, and etoposide (ICE) (BICE) versus ICE in patients with relapsed/refractory classical Hodgkin lymphoma (cHL).

II. To evaluate 2-year progression-free survival (PFS) in patients treated with 3 cycles of BICE versus ICE.

SECONDARY OBJECTIVES:

I. To compare positron emission tomography (PET) scan response after 3 cycles of BICE versus ICE chemotherapy.

II. To compare serum levels of tumor necrosis factor (TNF) proteins (a proliferation-inducing ligand \[APRIL\], B lymphocyte stimulator \[BLyS\], soluble \[s\]CD30, and CD40L) and CC thymus and activation-related cytokine (TARC) at baseline and after 3 cycles of BICE versus ICE chemotherapy.

III. To correlate baseline cytokine/chemokine levels with response to therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive bortezomib intravenously (IV) over 5 seconds on days 1 and 4, ifosfamide IV continuously over 24 hours on day 1, carboplatin IV over 1 hour on day 1, and etoposide IV over 2 hours on days 1-3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive ifosfamide, carboplatin and etoposide as in Arm A. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 2 years.

Arms:
arm 1: ARM A: Patients receive bortezomib IV over 5 seconds on days 1 and 4, ifosfamide IV continuously over 24 hours on day 1, carboplatin IV over 1 hour on day 1, and etoposide IV over 2 hours on days 1-3. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive ifosfamide, carboplatin and etoposide as in Arm A. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Bortezomib intervention 2: Carboplatin intervention 3: Etoposide intervention 4: Ifosfamide
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV

Protocol document:
Prot_SAP_000.pdf: 
STUDY PROTOCOL 
Protocol Number MDACC: 2008-0604 
 
A Randomized Phase II Study of Bortezomib Plus ICE (BICE) Versus Standard 
ICE for Patients with Relapsed/Refractory Classical Hodgkin Lymphoma  
 
Protocol Version: 
 
Date of Protocol: 
Original 1.5 
 
6/30/2010 
Investigator & Study Center: 
Michelle Fanale, MD 
UT MD Anderson Cancer Center 
Department of Lymphoma and Myeloma 
1515 Holcombe Blvd, Unit 429 
Houston, TX 77003-4009 
Telephone:  713-792-2860 
 
 
 
 
 
 
 
 
 
*VELCADE is the exclusive trademark of Millennium Pharmaceuticals, Inc., registered in the 
United States and internationally. 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 2 
PROTOCOL SUMMARY 
Title: A Randomized Phase II Study of Bortezomib Plus ICE (BICE) Versus Standard ICE for 
Patients with Relapsed/Refractory Classical Hodgkin Lymphoma  
 
Objectives 
The primary objectives of this study are to: 
• 
To determine the objective response rate (ORR), partial remissions (PR), and complete 
remissions (CR) after 3 cycles of bortezomib plus ICE (BICE) versus ICE in patients with 
relapsed/refractory classical Hodgkin lymphoma (cHL). 
• 
To evaluate 2-year progression-free survival (PFS) in patients treated with 3 cycles of BICE 
versus ICE. 
The secondary objectives of this study are to: 
• 
To compare PET scan response after 3 cycles of BICE versus ICE chemotherapy. 
• 
To compare serum levels of tumor necrosis factor (TNF) proteins (APRIL, BLyS, sCD30, and 
CD40L) and CC thymus and activation-related cytokine (TARC) at baseline and after 3 cycles of 
BICE versus ICE chemotherapy. 
• 
To correlate baseline cytokine/chemokine levels with response to therapy. 
Patient population 
Patients with relapsed/refractory cHL who have received prior front-line anthracyline-containing 
chemotherapy. Specific inclusion and exclusion criteria are detailed in section 3.2. 
Number of patients 
Maximum number of patients planned to enroll is 50. 
Study design and methodology 
Randomized study to 2 arms of therapy. Arm A is VELCADE or Bortezomib plus ICE (BICE) 
chemotherapy and Arm B is ICE (Ifosfamide, Carboplatin, and Etoposide) chemotherapy. Patients will 
have imaging done at baseline with CTs and PET/CT and then repeated after 3 cycles to assess response. 
Patients can also provide consent to participate in the optional correlative studies. For these studies blood 
will collected at baseline and after 3 cycles of therapy in order to perform serum protein analyses of TNF 
and TARC protein levels. 
Treatments administered 
Arm A: BICE: VELCADE on Day 1 and 4, ICE from Day 1 to 3, Neulasta on Day 5. 
Arm B: ICE from Day 1 to 3, Neulasta on Day 4. 
Efficacy data collected 
The following evaluations will be conducted to assess the efficacy of VELCADE: 
• 
CTs and PET/CT scans will be performed at baseline and after 3 cycles to assess response to 
treatment.  
Correlative studies collected (optional) 
• 
For patients who provide consent optional correlative studies will be performed. For these studies 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 3 
blood will collected at baseline and after 3 cycles of therapy in order to perform serum protein 
analyses of TNF and TARC protein levels. 
Safety data collected 
The following evaluations will be conducted to assess the safety of VELCADE:  
• 
Patients will undergo careful monitoring while on study. This includes weekly blood work and 
detailed parameters for retreatment as specified in the protocol including for absolute neutrophil 
count (ANC), platelet, bilirubin, alkaline phosphatase, AST, ALT, and creatinine. Additional 
safety monitoring is also incorporated for peripheral neuropathy for retreatment, as well as other 
non-hematologic, non-nephrologic, and non-hepatic toxicities.  
Statistical procedures 
 
The phase II part of this study is to compare ICE only and BICE in treating patients with classical 
Hodgkin lymphoma.  The primary outcome is complete remission.  The estimated accrual rate is 2 or 4 
patients per month.   A maximum of 50 patients will be accrued.  Patients will be evaluated for response 
after 0.75 months after receiving treatment for 3 cycles (14 days per cycle).  The patients will be 
randomized between ICE and BICE arms using a Bayesian adaptive algorithm.  In general, the trial will 
proceed as follows: The initial 20 patients will be randomized fairly with probability of 0.50 each 
between the two arms, so that the number of patients in each arm is equal at the start of the trial.  
Thereafter, as the trial proceeds patients will be randomized to the two groups with unequal probabilities 
in favor of the treatment that, on average, yields better response rate.  Consequently, each successive 
patient is more likely to receive the treatment with a better response rate, on average.  The details of the 
adaptive randomization scheme are as follows: 
Denote the response rate at each of the two treatment arms by {π1, π2} (1 for ICE, 2 for BICE).  Based on 
the currently available data, we assume the prior distribution for the response rate is π1 ~ Beta (0.5, 0.5) 
and π
2 ~ Beta (0.6, 0.4), respectively.  The resulting prior mean (95% credible interval) for ICE and BICE 
are 0.5(0.002, 0.99) and 0.6(0.007, 0.99), respectively.  After the initial first 20 patients being randomized 
to two treatment groups with an equal probability, each new patient will be randomized to receive 
treatment i with probability ρi=prob(πi > πj, j ≠i| Data), i, j=1,2.  If one of these two randomization 
probabilities falls below 0.025 then that arm will be dropped.  In addition, if prob(πi > 0.25|data) < 0.05, 
i.e. the data indicates that the response rate in that arm is highly unlikely to be larger than 0.25, then that 
arm will be dropped.  On the other hand, if one of the two randomization probabilities exceeds 0.975 then 
the trial will be terminated and that treatment arm will be selected.  If the trial does not stop early and the 
maximum 50 patients are accrued, a treatment is selected as being “better” if the probability that one 
treatment’s response rate is larger than the other’s response rate exceeds 0.95.   
 
Furthermore, serum levels of TNF proteins (APRIL, BLyS, sCD30, and CD40L) and TARC as 
determined at baseline compared to post-treatment with will be analyzed for both the BICE and ICE 
treatment groups by Mann-Whitney U test. Second, serum levels for each protein as determined at 
baseline compared to post-treatment will be analyzed for both the BICE and ICE treatment groups 
according to response rates as determined by IWG 1999 response criteria (CR, PR, SD, versus PD) by the 
Kruskal-Wallis test. Third, serum levels for each protein as determined at baseline compared to post-
treatment will be analyzed for both the BICE and ICE treatment groups according to PET scan results 
(PET negative versus PET positive) at completion of therapy by the Kruskal-Wallis test. Significance will 
be set for p ≤ 0.05.  
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 4 
TABLE OF CONTENTS 
1 
INTRODUCTION AND STUDY RATIONALE ............................................................ 10 
1.1 
Overview of the Disease ...................................................................................... 10 
1.2 
VELCADE (bortezomib) for Injection ................................................................ 10 
1.2.1 Scientific Background .............................................................................. 10 
1.2.2 Nonclinical Pharmacology ....................................................................... 11 
1.2.3 Nonclinical Toxicity ................................................................................ 11 
1.2.4 Clinical Pharmacokinetics and Pharmacodynamics ................................. 12 
1.2.5 Clinical Experience in Myeloma .............................................................. 12 
1.2.6 Potential Risks of VELCADE .................................................................. 14 
1.3 
VELCADE  (bortezomib) plus ICE for Classical HL .......................................... 19 
1.3.1 Rationale for BICE Treatment and Study Endpoints ............................... 19 
1.3.2 Preliminary Studies .................................................................................. 22 
1.3.3 Potential Risks of BICE (Bortezomib, Ifosfamide, Carboplatin, 
Etoposide) ................................................................................................ 24 
1.4 
Study Rationale and Selection of Drug Doses ..................................................... 30 
2 
STUDY OBJECTIVES .................................................................................................... 31 
2.1 
Primary Objective ................................................................................................ 31 
2.2 
Secondary Objectives ........................................................................................... 31 
3 
INVESTIGATIONAL PLAN .......................................................................................... 32 
3.1 
Overall Design and Plan of the Study .................................................................. 32 
 
 
3.1.1  Pretreatment Evaluations………………………………………………..32 
 
 
3.1.2 Evaluations During Treatment…………………………………………..32 
 
 
3.1.3 Duration of Treatment…………………………………………………..32 
 
 
3.1.4 Follow-up Evaluations…………………………………………………..33 
3.2 
Selection of Patients ............................................................................................. 34 
3.2.1 Inclusion Criteria ...................................................................................... 34 
3.2.2 Exclusion Criteria..................................................................................... 34 
3.3 
Study Treatments ................................................................................................. 35 
3.3.1 Clinical Trial Materials ............................................................................ 35 
3.3.2 Preparation, Handling, and Storage of Drugs .......................................... 35 
 
 
3.3.3    Drug Administration and Dosage Schedule …………………………….36 
3.3.4 Dose Modification and Delay .................................................................. 38 
3.3.5  Treatment Assignment ............................................................................. 39 
3.3.6 Packaging and Labeling ........................................................................... 39 
3.3.7 Concomitant Treatment ............................................................................ 40 
3.3.8 Treatment Compliance ............................................................................. 40 
3.4 
Duration of Treatment and Patient Participation ................................................. 40 
3.5 
Termination of Treatment and/or Study Participation ......................................... 41 
3.6 
Efficacy, Correlative studies, and Safety Measurements ..................................... 41 
3.6.1 Efficacy Measurements ............................................................................ 41 
3.6.2 Correlative Studies (optional) .................................................................. 43 
3.6.3 Safety Measurements ............................................................................... 43 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 5 
4 
ADVERSE EVENTS ....................................................................................................... 44 
4.1 
Definitions ............................................................................................................ 44 
4.1.1 Adverse Event Definition ......................................................................... 44 
4.1.2 Serious Adverse Event Definition ............................................................ 44 
4.2 
Procedures for AE and SAE Reporting ................................................................ 45 
4.3 
Monitoring of Adverse Events and Period of Observation .................................. 45 
4.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events .. 46 
5 
STATISTICAL PROCEDURES ..................................................................................... 47 
 
5.1 
Bayesian Adaptive Algorithm…………………………………………………...47 
 
5.2       Efficacy Analysis………………………………………………………………..48 
 
5.3  
Correlative TNF and TARC Serum Protein Level Analysis…………………….48 
6 
ADMINISTRATIVE REQUIREMENTS ........................................................................ 49 
6.1 
Good Clinical Practice ......................................................................................... 49 
6.2 
Ethical Considerations ......................................................................................... 49 
6.3 
Patient Information and Informed Consent .......................................................... 49 
6.4 
Patient Confidentiality ......................................................................................... 49 
6.5 
Protocol Compliance ............................................................................................ 49 
6.6 
On-site Audits ...................................................................................................... 50 
6.7 
Drug Accountability ............................................................................................. 50 
6.8 
Premature Closure of the Study ........................................................................... 50 
6.9 
Record Retention .................................................................................................. 50 
7 
REFERENCES ................................................................................................................. 51 
8 
APPENDICES ................................................................................................................. 56 
8.1 
Study Flow Chart ................................................................................................. 57 
8.2 
ECOG Performance Status Scale ......................................................................... 60 
8.3 
Body Surface Area Calculation ............................................................................ 61 
8.4 
New York Heart Association Classification of Cardiac Disease ......................... 62 
8.5 
Declaration of Helsinki ........................................................................................ 63 
8.6 
Common Terminology Criteria for Adverse Events Version 3.0 ........................ 67 
8.7 
FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 ...................................... 68 
8.8       Outside Physician Participation During Treatment 
 
 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 6 
LIST OF TABLES AND FIGURES IN THE TEXT 
Tables 
Table 1  
Known Anticipated Risks of VELCADE by MedDRA System Organ Class, 
Observed Incidence, and Preferred Term…………………………………….14 
Table 2  
Reports of Adverse Reactions from Postmarketing Experience……………...18 
Table 3 
Arm A Treatment with BICE………………………………………………...36 
Table 4 
Arm B Treatment with ICE…………………………………………………..37 
Table 5 
Management of Patients with VELCADE Related Peripheral Sensory or Motor 
Neuropathy at Retreatment…………………………………………………...38 
Table 6  
1999 IWG Response Criteria………………………………………………....41 
 
Table 7 
2007 IWG Response Criteria…………………………………………………41 
 
Table 8 
Operating Characteristics for the Adaptive Randomization When 2 Patients  
Are Accrued Per Month………………………………………………………47 
 
Figures 
Figure 1A&B  Signaling Between Microenvironment and the Reed-Sternberg Cells………..22 
Figure 2A&B  BICE and ICE Treatment Schema and Determination of Response………......33 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 7 
ABBREVIATIONS LIST 
Abbreviation 
Definition 
°C 
degrees Celsius 
μM 
micromolar 
20S 
20S proteasome subunit 
AE 
adverse event 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
ASCT 
autologous stem cell transplant 
ASH 
American Society of Hematology 
Bc1-2 
B-cell lymphoma-2; a gene that inhibits apoptosis 
BICE 
Bortezomib (VELCADE), Ifosfamide, Carboplatin, and 
Etoposide 
BSA 
body surface area 
CAM 
cell adhesion molecules  
cHL 
classical Hodgkin lymphoma 
CLL 
chronic lymphocytic leukemia 
cm 
centimeter 
CR 
complete response or remission 
CT 
computed tomography 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
dL 
deciliter 
DLT 
Dose Limiting Toxicity 
DNA 
deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
EFS 
event-free survival 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HDAC 
histone deacetylase  
ht 
height 
ICE 
Ifosfamide, Carboplatin, and Etoposide 
IκB 
I kappa B kinase; cytokine response kinase that activates 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 8 
Abbreviation 
Definition 
transcription factor NF-kappa b at serine 32 and 36 
ICAM-1 
intercellular adhesion molecule 1 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IPS 
International Prognostic Score 
IRB 
Institutional Review Board 
IV 
intravenous 
IκBα 
I kappa B alpha-associated protein kinase 
IWG 
International Working Group 
kg 
kilogram 
Ki 
inhibitory constant 
lbs 
pounds 
m2 
square meters 
mg 
milligram 
min 
minute 
mL 
milliliter 
mm3 
cubic millimeters 
mmol 
millimole 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NF-κB 
nuclear factor-κB 
ng 
nanogram 
NHL 
non-Hodgkin lymphoma 
nM 
nanomole 
OS 
overall survival 
p21 
p21(ras) farnesyl-protein transferase 
p27 
cyclin-dependent kinase inhibitor 
p53 
tumor suppressor protein with molecular weight of 53 kDa 
PD 
progression of disease 
PET 
positron emission tomography 
PFS 
progression-free survival 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 9 
Abbreviation 
Definition 
PR 
partial response or remission 
RS cells 
Reed-Sternberg cells 
SAE 
serious adverse event 
SD 
stable disease 
TNF 
tumor necrosis factor 
TARC 
CC thymus and activation-related cytokine 
US 
United States 
USP 
United States Pharmacopeia 
VCAM-1 
vascular cell adhesion molecule 1 
w/w 
weight-to-weight ratio 
wt 
weight 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 10 
1 INTRODUCTION AND STUDY RATIONALE 
1.1 Overview of the Disease 
1.1.1  Relapsed/Refractory Classical Hodgkin Lymphoma 
Although Hodgkin lymphoma (HL) is considered highly curable, up to 15% of stage I/II and 
40% of stage III/IV patients will experience relapse, and 10-15% of patients will have primary 
refractory disease. This paired with the incidence in patients who are in their 20s to 30s makes 
successful treatment of relapsed/refractory disease of critical importance. Only patients who 
obtain a positive response to 2
nd-line chemotherapy followed by an autologous stem cell 
transplant (ASCT) have the potential of long-term disease-free survival. In addition, patients who 
achieve complete remission with 2nd-line chemotherapy prior to ASCT have higher disease-free 
survivals than those who do not (Moskowitz et al., 2001).  
1.2  VELCADE (bortezomib) for Injection 
1.2.1  Scientific Background 
VELCADE™ (bortezomib) for Injection is a small molecule proteasome inhibitor developed by 
Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies.  
VELCADE is currently approved by the United States Food and Drug Administration (US FDA) 
and it is registered in Europe for the treatment of multiple myeloma patients front-line and 
relapsed and mantle cell lymphoma patients who have received at least 1 prior therapy. 
  
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 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 
κB (NF-κB) 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). 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 11 
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 (t½α <10 minutes) followed by a longer elimination phase (t½β 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 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. 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 12 
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. 
1.2.5  Clinical Experience in Myeloma 
It is estimated that more than 55,000 patients have been treated with VELCADE, including 
patients treated through Millennium-sponsored clinical trials, Investigator-Initiated Studies, the 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 13 
US NCI Cancer Therapy Evaluation Program (CTEP), and with commercially available drug.  
VELCADE has been commercially available since 13 May 2003. 
 
The overall goal of the Millennium phase I program was to determine the MTD and dose-
limiting toxicity (DLT) of VELCADE in a number of therapeutic settings involving subjects 
with various advanced malignancies.  In a Phase I trial in patients with refractory hematologic 
malignancies, the MTD for a twice weekly for 4 weeks of a 42 day cycle was 1.04 mg/m2/dose, 
with DLTs of thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise (Orlowski et 
al., 2002).  The toxicity was greatest during the third and fourth weeks of therapy. In the 3-week 
schedule of VELCADE 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 VELCADE monotherapy, the MTD was 1.6 
mg/m2/dose and DLT included hypotension, tachycardia, diarrhea, and syncope.  
  
In phase 1 clinical studies, anti-tumor activity was reported in subjects with NHL, multiple 
myeloma, Waldenström’s Macroglobulinemia, squamous cell carcinoma of the nasopharynx, 
bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate cancer. 
The safety and efficacy of VELCADE in subjects with multiple myeloma were investigated in 
two phase 2 clinical studies, studies M34100-024 (subjects with first relapse) (Jagannath et al, 
2004) and M34100-025 (subjects with second or greater relapse and refractory to their last prior 
therapy) (Richardson et al, 2003).  In M34100-025, 202 heavily pre-treated subjects with 
refractory multiple myeloma after at least 2 previous treatments received VELCADE, 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 Blade (Blade et al., 1998) were utilized to 
determine disease response.  CRs were observed in 4% of subjects, with an additional 6% of 
patients meeting all criteria for CR but having a positive immunofixation test.  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) (Richardson et al, 2005), also referred to as the APEX study, 
was designed to determine whether VELCADE 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 VELCADE relative to high-dose dexamethasone, and whether treatment with VELCADE 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 (VELCADE: 331; 
dexamethasone: 332).  Patients randomized to VELCADE received 1.3 mg/m2 I.V. push twice 
weekly on days 1, 4, 8, and 11 of a 3-week cycle for up to eight treatment cycles as induction 
therapy, followed by 1.3 mg/m2 VELCADE weekly on days 1, 8, 15, and 22 of a 5-week cycle 
for three 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 
four treatment cycles as induction therapy, followed by dexamethasone 40 mg once daily on 
days 1 to 4 followed of a 4-week cycle for five cycles as maintenance therapy. The European 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 14 
Group for Blood and Marrow Transplant (EBMT) response criteria, as described by Blade 
(Blade et al., 1998) were utilized to determine disease response.  There was a 78% increase in 
TTP for the VELCADE arm. Median TTP was 6.2 months for the VELCADE arm and 3.5 
months for the dexamethasone arm (P<.0001). CR (complete response) + PR (partial response) 
was 38% with VELCADE vs. 18% with dexamethasone (P<.0001). CR was 6% with VELCADE 
vs. <1% with dexamethasone (P<.0001). The CR + nCR rate was13% with VELCADE vs. 2% 
with dexamethasone. In patients who had received only one prior line of treatment (VELCADE: 
132; dexamethasone: 119), CR + PR was 45% with VELCADE vs. 26% with dexamethasone 
(P=.0035). With a median 8.3 months of follow-up, overall survival was significantly longer 
(P=.0013) for patients on the VELCADE arm vs. patients on the dexamethasone arm. The 
probability of survival at one year was 80% for the VELCADE arm vs. 66% for the 
dexamethasone arm, which represented a 41% decreased relative risk of death in the first year 
with VELCADE (P=.0005). In patients who had received only one prior line of treatment, the 
probability of survival at one year was 89% for the VELCADE arm vs. 72% for the 
dexamethasone arm, which represented a 61% decreased relative risk of death in the first year 
with VELCADE (P=.0098). Updated response rates and survival data were reported for 
M34101-039 (Richardson ASH, 2005). The updated CR (complete response) + PR (partial 
response) rate was 43% with VELCADE. The CR + nCR rate was 16% with VELCADE. With a 
median 22 months of follow-up, overall survival was significantly longer for patients on the 
VELCADE arm vs. patients on the dexamethasone arm. The median overall survival was 29.8 
months (95% CI: 23.2, not estimable) for the VELCADE 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 
one year was 80% for the VELCADE arm vs. vs 67% for the dexamethasone arm (P=0.0002).    
 
Studies using VELCADE as monotherapy and in combination with other chemotherapy agents 
are continuing.   
1.2.6  Potential Risks of VELCADE 
More than 55,000 people have been exposed to VELCADE.  
Table 1    
Known Anticipated Risks of VELCADE 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 that may increase the risk of 
bleeding*, anemia* 
Very common  
Neutropenia* 
Common  
Lymphopenia, pancytopenia*, leukopenia* 
Uncommon 
Febrile neutropenia 
Cardiac Disorders 
Common  
Arrhythmias including tachycardia, atrial fibrillation, 
and palpitations; acute development or exacerbation of 
cardiac failure, including congestive heart failure*; 
pulmonary edema* 
Uncommon 
Cardiogenic shock*, new onset of decreased left 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 15 
ventricular fraction*, atrial flutter, cardiac tamponade*, 
bradycardia, atrioventricular block (complete), cardiac 
arrest, cardiopulmonary failure 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impairment 
Eye Disorders 
Common  
Blurred vision, conjunctival infection and irritation 
Uncommon 
Conjunctival hemorrhage 
Gastrointestinal Disorders 
Most common 
Constipation, diarrhea*, nausea, vomiting* 
Very common  
Gastrointestinal and abdominal pain, excluding oral and 
throat 
Common  
Dyspepsia, pharyngolaryngeal pain, gastroesophageal 
reflux, abdominal distension, stomatitis and mouth 
ulceration, dysphagia, gastrointestinal hemorrhage 
(upper and lower gastrointestinal tract)*, rectal 
hemorrhage (includes hemorrhagic diarrhea) 
Uncommon 
Eructation, tongue ulceration, retching, upper 
gastrointestinal hemorrhage*, hematemesis*, oral 
mucosal petechiae, ileus paralytic*, odynophagia, 
enteritis, colitis, oesphagitis, fungal oesphagitis, 
enterocolitis, acute pancreatitis*, gastritis 
General Disorders and Administration Site Conditions 
Most common 
Asthenic conditions, including weakness, fatigue, 
lethargy, and malaise; pyrexia 
Very common  
Rigors, edema of the lower limbs 
Common  
Neuralgia, chest pain, mucosal inflammation* 
Uncommon 
Injection site pain and irritation, injection site phlebitis, 
general physical health deterioration*, injection site 
cellulitis, catheter site cellulitis, injection site infection 
Hepatobiliary Disorders 
Common  
Abnormal liver function tests 
Uncommon 
Hyperbilirubinemia, hepatitis* 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 16 
Infections and Infestations 
Very common  
Upper respiratory tract infection, nasopharyngitis, lower 
respiratory tract and lung infections*, pneumonia*, 
Herpes zoster* 
Common  
Herpes zoster disseminated,*, postherpetic neuralgia, 
sinusitis, pharyngitis, oral candidiasis, urinary tract 
infection*, catheter-related infection*, sepsis and 
bacteremia*, cellulitis and other skin infections*, Herpes 
simplex 
Uncommon 
Bronchitis, gastroenteritis*, septic shock*, urosepsis*, 
aspergillosis*, tinea infections, Herpes zoster 
ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic, varicella, empyema 
Injury, Poisoning, and Procedural Complications  
Common  
Catheter-related complication 
Uncommon 
Subdural haematoma 
Investigations 
Common  
Increased ALT, increased AST, increased alkaline 
phosphatase 
Uncommon 
Increased GGT, oxygen saturation decreased*, blood 
albumin decreased 
Metabolism and Nutritional Disorders 
Most common 
Decreased appetite and anorexia, which may result in 
dehydration and/or weight loss 
Very common  
Dehydration* 
Common  
Hyperglycemia, hypoglycemia, hyponatremia, 
hypokalemia, hypercalcemia* 
Musculoskeletal and Connective Tissue Disorders 
Very common  
Bone pain, pain in limb, myalgia, arthralgia 
Nervous System Disorders 
Most common 
Peripheral neuropathy (including all preferred terms 
under the MedDRA high-level term peripheral 
neuropathy NEC) 
Very common  
Paresthesia and dysesthesia; dizziness, excluding 
vertigo; headache 
Common  
Polyneuropathy, syncope, dysgeusia 
Uncommon 
Convulsions, loss of consciousness, ageusia, 
encephalopathy, paralysis*, reversible posterior 
leukoencephalopathy syndrome, autonomic neuropathy 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps)
Uncommon 
Tumor lysis syndrome* 
Psychiatric Disorders 
Very common 
Anxiety  
Common 
Confusion, insomnia  
Uncommon 
Delirium 
Renal and Urinary Disorders 
Common 
Renal impairment, including renal failure and increased 
serum creatinine*; hematuria 
Uncommon 
Difficulty in micturition 
Respiratory, Thoracic, and Mediastinal Disorders 
Very common 
Cough, dyspnea  
Common 
Epistaxis, exertional dyspnea, pleural effusion*, 
rhinorrhea, hypoxia* 
Uncommon 
Hemoptysis*, acute respiratory distress*, respiratory 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 17 
failure*, pneumonitis*, lung infiltrates, pulmonary 
alveolar hemorrhage*, interstitial lung disease*, 
pulmonary hypertension*, pleurisy, pleuritic pain 
Skin and Subcutaneous Tissue Disorders 
Very common 
Skin rash, which can be pruritic, erythematous, and can 
include evidence of leukocytoclastic vasculitis 
Common 
Urticaria 
Uncommon 
Leukocytoclastic vasculitis 
Vascular Disorders 
Very common 
Hypotension* 
Common 
Orthostatic/postural hypotension, petechiae 
Uncommon 
Cerebral hemorrhage* 
Most common = ≥ 30%, Very common = 10% to 29%, Common=1% to 9%, Uncommon= < 1%,  
* Fatal outcomes have been reported 
Abbreviations:   ALT = alanine transaminase; AST = aspartate transaminase; GGT = gamma glutamyl 
transferase 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 18 
Table 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 
 
Cardiac tamponade 
Rare 
Rare 
Ear and labyrinth disorders 
 
 
Deafness bilateral 
Rare 
Eye Disorders 
 
 
Ophthalmic herpes 
Rare 
Gastrointestinal Disorders 
 
 
Acute pancreatitis  
 
Ischemic colitis 
Rare 
Rare 
Hepatobiliary disorders 
 
 
Hepatitis 
 
Liver failure 
Uncommon 
Unknown 
Infections and infestations 
 
 
Herpes meningoencephalitis 
Rare 
Immune System Disorders 
 
 
Angioedema 
Rare 
Nervous System Disorders 
 
 
Autonomic neuropathy 
 
Dysautonomia 
 
Encephalopathy 
Rare 
Unknown 
Rare 
Respiratory, thoracic and mediastinal disorders: 
 
 
Acute diffuse infiltrative pulmonary disease  
 
Acute respiratory distress syndrome (ARDS) 
 
Interstitial pneumonia 
 
Pneumonitis 
Rare 
Unknown 
Unknown 
Unknown 
Skin and subcutaneous system disorders 
 
 
Toxic epidermal necrolysis 
Unknown 
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). 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 19 
 
Other medical events of interest that are considered not causally related to VELCADE include 
hepatic failure and QT prolongation.  Fatal outcomes have been reported. 
Women of childbearing potential should avoid becoming pregnant while being treated with 
VELCADE.  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 VELCADE may be found in the Investigator’s 
Brochure. 
1.3  VELCADE (bortezomib) plus ICE for Classical HL  
1.3.1   Rationale for BICE Treatment and Study Endpoints 
1.3.1a Outcomes for ICE followed by ASCT for relapsed/refractory classical HL  
Salvage treatment of relapsed/refractory Hodgkin lymphoma patients with 2nd-line chemotherapy 
with ICE followed by an autologous stem cell transplant results in a 40 to 60% long-term event-
free survival rate. In addition, patients who have evidence of CR after ICE have a 20% 
improvement in event-free survival compared to patients in PR and approximately 20-25% of 
patients achieve CR as evaluated by International Working Group (IWG) 1999 CT criteria after 
2-3 cycles of ICE (Moskowitz et al., 2001; Abali et al., 2008). 
1.3.1b Significance of PET scans in early response assessment and prediction of outcomes  
 
PET scans have emerged as a powerful method of response rate assessment in lymphoma. The 
key advantage of PET scans over CT scans is the ability to distinguish between viable tumor and 
necrosis or fibrosis present after completion of treatment. This is particularly important in HL 
patients who often can present with bulky and/or mediastinal masses which commonly result in 
residual masses on CT scan after treatment completion. Given this positive benefit the 1999 IWG 
criteria (Cheson et al., 1999) for response assessment of malignant lymphoma were updated in 
2007 with CR now being assessed if PET scan positive areas prior to treatment have become 
PET scan negative regardless of size (Cheson et al., 2007). This is in striking difference to the 
original IWG criteria published in 1999 which for CR requires the complete disappearance of all 
detectable radiographic evidence of disease on CT scans (Cheson et al., 1999).  
 
PET-based criteria are now routinely used in HL to assess response to front-line therapy. PET 
scan response has been shown to predict progression-free survival (PFS) and overall survival 
(OS) after 2 cycles of chemotherapy with a 2-year PFS in PET negative patients of 96% 
compared to 0% for PET positive patients (Hutchings et al., 2006). In addition, recent analysis 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 20 
has shown that PET scan assessment after course 2 of ABVD (adriamycin, bleomycin, 
vinblastine, dacarbazine) chemotherapy is better than the commonly referenced International 
Prognostic Score (IPS) in prognostic value with 2-year PFS of 95% for those with negative PET 
scans after cycle 2 of treatment compared to 13% for those with positive PET scans (Gallamini et 
al., 2007).  
 
1.3.1c Relevance of PET scans for response assessment in relapsed/refractory cHL patients  
 
While substantial data exists for the use of PET scans and the revised 2007 IWG criteria in the 
front-line setting, the use of PET scans in the relapsed/refractory 2nd-line and higher treatment 
setting is still being defined. Emerging data however shows that there is prognostic significance 
of PET scan response pre-ASCT in predicting outcomes post-ASCT (Seam et al., 2007). In a 
retrospective clinical study  in lymphoma patients undergoing ASCT the event-free survival 
(EFS) rate was 80% in patients who had negative pre-ASCT PET images as compared to 43% in 
patients who had positive pre-ASCT PET images (Filmont et al., 2007). Another study showed 
retrospectively that the median PFS was 19 months for patients with negative pre-ASCT PET 
scans as compared to 5 months for patients with positive pre-ASCT PET scans (Svoboda et al., 
2006). It has also been demonstrated that early PET assessment after 2 cycles of 2nd-line 
chemotherapy in combination with their recurring Hodgkin score (Josting et al., 2002) was 
useful in identifying four categories of risk for relapse after ASCT (Schot et al., 2007). Further 
evaluation of PET scan response in a prospective clinical trial holds the ability to further define 
the relevance of PET scan response pre-ASCT after 2nd-line chemotherapy through correlation 
with PFS. 
 
1.3.1d Significance of the diversity of the nuclear factor (NF)-κB signaling pathway  
           and activation through TNF receptor binding  
 
The importance of NF-κB signaling was first identified in multiple myeloma and led to the 
development and approval of bortezomib. Data has now emerged which supports the role of both 
classical (canonical) and alternative (noncanonical) NF-κB pathways. The diversity of these 
pathways allow for NF-κB activity even in the setting of genetic abnormalities. The classical 
pathway when activated results in nuclear translocation of the heterodimer of p50/p65 while the 
alternative pathway results in nuclear translocation of the heterodimer of p52/relB. Bortezomib 
blocks proteasome degradation of phosphorylated IκBα and p100 in respectively the classical 
and alternative pathways, and thus prevents nuclear translocation of the p50/65 and p52/relB 
heterodimers and inhibits NF-κB activity.  Furthermore, the TNF receptor family which includes 
BCMA, TACI, BR3, CD30, and CD40 have been shown to be able to activate the NF-κB 
pathway (Annunziata et al., 2007).  
 
1.3.1e Significance of the interdependence of Reed-Sternberg cells on the microenvironment.  
 
The unique biology of Hodgkin lymphoma is related to the interdependence of the rare RS cells 
with the surrounding microenvironment (Figure 1). This microenvironment is composed of B 
and T cells and macrophages which provide survival signals to the RS cells and thus support 
Hodgkin lymphoma tumor growth. The TNF superfamily of proteins has a key role in the 
microenvironment cross-signaling with the RS cells and is composed of APRIL, BLyS, 
CD30L/CD30, and CD40L/CD40.  


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 21 
 
APRIL and BLyS are TNF ligands which have important roles in the both malignant and benign 
B cell function and are expressed by macrophages which surround RS cells. APRIL and BLyS 
bind to BCMA and TACI and BLyS can bind a third receptor BR3 (Bossen et al., 2006). These 
receptors are found on both normal and malignant B cells, including chronic lymphocytic 
leukemia (CLL) cells and Hodgkin RS cells. In CLL BLyS was found to bind to BR3 and 
activate the alternative NF-κB pathway, while BLyS and APRIL were found to bind to BCMA 
and TACI and activate the classical NF-κB pathway (Endo et al., 2007). Similar to RS cells CLL 
cells are also dependent on cytokine support from nurselike cells in the microenvironment which 
also express high levels of ARRIL and BLyS. In a retrospective non-Hodgkin lymphoma (NHL) 
study, serum BLyS levels at time of diagnosis were found to correlate with disease outcome with 
patients who had BLyS levels > 40 ng/mL having a poorer median overall survival. In addition, 
BLyS levels increased in patients after transformation of follicular lymphoma to large B cell 
lymphoma suggesting the BLyS expression may also correlate with disease severity (Novak et 
al., 2004). 
 
CD30 has dense expression on RS cells, but rare expression on normal cells (Yazbeck et al., 
2006). Benefit has been seen in HL clinical trials which have targeted CD30 through antibodies 
or antibody-drug conjugates (Ansell et al., 2007; Bartlett et al., 2008; Hamblett et al., 2005). 
CD30L (CD153) is a transmembrane protein which is expressed by the surrounding B and T 
cells, but is not expressed by RS cells and has paradoxical effects on cell survival when 
compared to CD30 by inducing cell death of CD30 RS cells.  In addition, the soluble form of 
CD30 (sCD30) has been found to be an independent negative prognostic factor for event-free 
survival (EFS) and is thought to potentially protect CD30 tumor cells from CD30L induced 
apoptosis (Younes et al., 1997). In a retrospective analysis of HL patients treated with front-line 
chemotherapy a baseline sCD30 level of ≥ 100 U/mL as compared to ≤ 100 U/mL predicted for a 
5-year EFS of 60% versus 88% (Nadali et al., 1998).  
 
CD40 expression is less restricted that CD30 and is expressed by B and T cells and the Hodgkin 
RS cells. RS cells do not express CD40L (CD154), but receive CD40L signals from the 
surrounding microenvironment. CD40 can be targeted for the treatment of HL and NHL, and 
currently two antibodies are being evaluated for treatment (Forero-Torres et al., 2006; Hsu et al., 
2006). While the role of soluble CD40L in predicting prognosis has not yet been fully evaluated 
in lymphoma, prognostic significance has been demonstrated in patients with acute coronary 
syndromes. Soluble CD40L is shed from stimulated lymphocytes and released after platelet 
stimulation, and soluble CD40L > 5 μg/L in patients with unstable coronary artery disease 
identified patients at increased risk of further coronary events and those who would benefit from 
antiplatelet therapy (Heeschen et al., 2003).  
 
Although not a TNF family protein, CC thymus and activation-related cytokine (TARC) is a 
protein highly produced by RS cells and antigen-presenting cells and attracts T cells by 
stimulating the CC chemokine receptor 4 (CCR4). Thus, TARC is thought to have a role in 
allowing RS cells to provide positive feedback to the microenvironment T cells. A retrospective 
study of HL patients treated with front-line chemotherapy demonstrated the prognostic 
significance of baseline TARC levels with levels of > 2,000 pg/mL being correlated with a 
higher rate of relapse and inferior survival (Weihrauch et al., 2005).  


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 22 
 
1.3.1f Relevance of APRIL, BLyS, sCD30, CD40L, and TARC to predict response  
          in relapsed/refractory HL treatment 
 
The clinical significance of baseline serum levels of BLyS, sCD30, and TARC have been 
retrospectively evaluated in patients receiving front-line treatment for lymphoma (Novak et al., 
2004; Nadali et al., 1998; Weihrauch et al., 2005; Oki et al., 2007). However, the significance of 
baseline and post-2nd-line treatment values in the relapsed/refractory setting has not yet been 
determined. Further evaluation holds potential value of developing surrogate markers to predict 
radiographic response to chemotherapy. 
 
 
 
 
 
 
Figure 1A&B: Signaling Between Microenvironment and the Reed-Sternberg Cells The 
microenvironment consisting of B and T cells with macrophages provide cytokine signaling to 
the Hodgkin RS cells and allow for activation of the classical and alternative pathways of NF-
κB. 
 
1.3.2  Preliminary Studies 
We have previously evaluated bortezomib both preclinically and clinically, shown that PET scan 
negativity in HL correlates with EFS, and have demonstrated the potential role of serum levels of 
BLyS and TARC as prognostic and predictive markers. 
 
1.3.2a Preclinical evaluation of bortezomib in HL cells 
 
Bortezomib demonstrated high antiproliferative activity by cell cycle arrest at the G2-M  
phase and induced apoptosis. These effects were independent of mutations in IκBα. Treatment 
with bortezomib activated the caspase cascade, increased p21 and Bax levels, decreased Bcl-2 
levels, and enhanced the effect of gemcitabine (Zheng et al., 2004). 
 
1.3.2b Pilot Clinical Evaluation of Bortezomib in Heavily Pretreated HL Patients 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 23 
14 patients with HL who were refractory to their last treatment were treated with 1.3 mg/m2 of 
bortezomib on days 1, 4, 8, and 11 of a 21-day cycle. Patients had received a median of 4 prior 
treatment regimens and 93% of patients were previously treated with ASCT. One patient who 
had received 9 prior treatments and had extensive pulmonary, splenic, and nodal involvement 
achieved a PR and 2 patients had stable disease (SD). These results suggested low single-agent 
activity in heavily pretreated patients with similar results seen in three other HL trials, but a 
combination treatment with chemotherapy was planned to evaluate activity in less heavily 
pretreated patients (Younes et al., 2006; Trelle et al., 2006; Blum et al., 2006; Stauss et al., 
2006). 
 
1.3.2c Phase I study of bortezomib Plus ICE (BICE) for patients with  
           relapsed/refractory classical HL (MDACC 2006-0527) 
 
Combined therapies with bortezomib in myeloma and solid tumors have shown positive results, 
including with platinum-based chemotherapy (San Miguel et al., 2008; Palumbo et al., 2007; 
Davies et al., 2004; Fanucchi et al., 2006). Thus we designed this clinical study to evaluate BICE 
as 2nd-line treatment for patients with relapsed/refractory HL. Bortezomib was given on Days 1 
and 4 and ICE was given on Days 1 to 3 with Neulasta given on Day 5. Dose levels of 
bortezomib were 0 = 1.0 mg/m2, 1 = 1.3 mg/m2, and 2 = 1.5 mg/m2. Cycles were repeated on 
Day 14 if ANC ≥ 1000 cells/m3 and platelets ≥ 100,000 cells/m3. After 3 cycles patients were 
evaluated for response by CTs and PET. Hematologic DLT was defined as grade 4 
thrombocytopenia or neutropenia lasting greater than 14 days.  
 
Median age of patients was 32 and 42% of patients had primary refractory disease. To date 12 
patients are evaluable for toxicity and 12 patients for response. By 1999 IWG response criteria 
there are 4/12 CR/CRu, 5/12 PR, and 3/12 progressive disease (PD). All patients with PD had 
primary refractory disease. PET scans post-treatment were negative for 9/12 patients (CR + PR 
1999 IWG response criteria patients). To date 8/9 patients have completed ASCT (1 patient 
declined ASCT). No 2nd phereses have been needed for stem cell collection. Reversible grade 4 
neutropenia and thrombocytopenia occurred in respectively 40% and 50% of the patients. 
Median day for retreatment was Day 20 for cycle 2 and Day 21 for cycle 3. There were no 
toxicities of peripheral neuropathy, febrile neutropenia, or infection (Fanale et al., 2008).  
 
 
1.3.2d Depletion of B cells from the microenvironment improves efficacy of ABVD and EFS 
 
Rituximab (R) depletes B cells from the microenvironment and R plus ABVD is believed to 
increases responses by decreasing survival factors that stimulate RS cell growth. Of the 70 
patients enrolled in this front-line study 50% had stage II disease and 50% had stage III/IV 
disease. By the IPS model 55% had a score of 2 or higher. Rituximab was given weekly for the 
first 6 weeks to the standard dose and schedule of ABVD. R-ABVD improved EFS in all patients 
but had the highest benefit in those with IPS > 2 with an EFS of 77%. PET also became negative 
in 78% of patients after 2 to 3 cycles of R-ABVD which corresponded to a 5-year EFS of 93% 
for those who were PET negative and 75% for those who were PET positive (Wedgwood et al., 
2007). 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 24 
1.3.2e Serum BLyS level as a prognostic factor in front-line HL treatment 
 
Serum samples were obtained in 93 healthy volunteers and 50 patients with HL. ELISA was used 
to assess BLyS levels. Levels of BLyS in healthy volunteers had a median value of < 0.3 ng/mL 
and in newly diagnosed patients had a median value of 2.0 ng/mL. Newly diagnosed patients 
who had a serum BLyS level of ≥ 2.0 ng/mL had shorter 2-year PFS than those who had BLyS 
levels of < 2.0 ng/mL at respectively 64% versus 100% (Oki et al., 2007).  
 
1.3.2f Serum TARC levels decrease with clinical responses to HDAC inhibition  
          in relapsed/refractory HL treatment 
 
MGCD0103 is an oral histone deacetylase (HDAC) inhibitor. In a phase II clinical study patients 
were treated with doses 3 times a week in 4 week cycles and serum TARC levels were 
determined by ELISA prior to starting treatment and on Day 8. Serum TARC levels decreased by 
at least 40% in 5 patients and all achieved responses of CR + PR. Thus, early decreases of TARC 
levels were shown to potentially predict response to treatment (Younes et al., 2007). 
 
1.3.3 Potential Risks of BICE (Bortezomib, Ifosfamide, Carboplatin, Etoposide) 
 
1.3.3a Bortezomib (VELCADE) 
 
See section 1.2.6 for details. 
 
1.3.3b Ifosfamide 
 
• Common Trade Names 
o Ifex 
• Class 
o Alkylating Agent  
o Antineoplastic Agent  
o Nitrogen Mustard 
• FDA-Labeled Indications 
o Testicular cancer, germ cell, third-line in combination with other agents 
o (Hodgkin lymphoma is a non-FDA labeled indication) 
• Dose Adjustments 
o None formally listed 
• Administration 
o administer as a slow IV infusion over at least 30 min  
o reconstituted solution may be diluted with D5W, NS, LR, or Sterile Water for 
Injection to a final concentration of 0.6 to 20 mg/mL  
o reconstitute powder with Sterile Water for Injection or Sterile Bacteriostatic 
Water for Injection to a final concentration of 50 mg/mL  


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 25 
• Monitoring 
o CBC; prior to each dose and during therapy  
o urinalysis; prior to each dose and during therapy  
o serum chemistries including phosphorous, alkaline phosphatase, and other 
appropriate laboratory studies  
• How Supplied 
o Intravenous Powder for Solution: 1 GM, 3 GM 
• Contraindications 
o hypersensitivity to ifosfamide or mesna products  
o severe bone marrow depression 
• Precautions 
o extravasation  
o hemorrhagic cystitis  
o may inhibit wound healing  
o neurologic manifestations requiring discontinuation of therapy (coma, 
confusion, hallucinations, somnolence)  
o patients with impaired renal function and/or prior exposure to cisplatin  
o potentially carcinogenic and mutagenic  
o pregnancy  
o severe myelosuppression (given with other chemotherapy agents)  
o total ifosfamide doses above 49.6 to 100 grams/m(2), especially in pediatric 
patients  
o use proper procedures for handling and disposal of chemotherapy   
• Adverse Events 
o COMMON 
 Dermatologic: Alopecia  
 Gastrointestinal: Nausea and vomiting (58% ) 
o SERIOUS 
 Endocrine metabolic: Metabolic acidosis (31%)  
 Hematologic: Myelosuppression  
 Neurologic: Neurotoxicity (12%)  
 Renal: Disorder of urinary tract, Nephrotoxicity (6%) 
 
1.3.3c MESNA 
• Common Trade Names 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 26 
o Mesnex 
• Class 
o Hemorrhagic Cystitis Inhibitor 
• FDA-Labeled Indications 
o Prophylaxis for Ifosfamide-induced hemorrhagic cystitis 
• Dose Adjustments 
o None formally listed 
• Administration 
o administer as an IV bolus injection  
o can dilute with D5W, NS, or LR to a final concentration of 20 mg/mL  
• Monitoring 
o urine, for presence of hematuria; every morning prior to ifosfamide therapy  
o nausea, vomiting, and diarrhea 
• How Supplied 
o Intravenous Solution: 100 MG/ML 
• Contraindications 
o hypersensitivity to mesna/other thiol compounds 
• Precautions 
o None formally listed 
• Adverse Events 
o COMMON 
 Gastrointestinal: Nausea and vomiting  
 Neurologic: Headache, Pain in limb  
 Other: Fatigue 
o SERIOUS 
 Cardiovascular: Hypotension 
 
1.3.3d Carboplatin 
 
• Common Trade Names 
o Paraplatin 
• Class 
o Antineoplastic Agent  
o Platinum Coordination Complex 
• FDA-Labeled Indications 
o Ovarian cancer, Advanced (as initial treatment in combination with other 
approved chemotherapy agents) 
o Ovarian cancer, Advanced (palliative treatment of recurrent disease) 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 27 
o (Hodgkin lymphoma is a non-FDA labeled indication)  
• Dose Adjustments 
o hematologic: dosage adjustments in single-agent or combination therapy are 
based on the lowest post-treatment platelet and neutrophil counts- for platelets 
greater than 100,000/neutrophils greater than 2,000, adjusted dose is 125% 
from prior course; for platelets less than 50,000/neutrophils less than 500, 
adjusted dose is 75% from prior course  
o renal impairment: for the initial course of therapy- CrCl 41-59 mL/min give 
250 mg/m(2); CrCl 16-40 mL/min give 200 mg/m(2)  
• Administration 
o (infusion) administer over 15 minutes or longer; pre- or post-treatment 
hydration or forced diuresis is not required  
o may be further diluted to concentrations as low as 0.5 mg/mL with D5W or 
NS; use within 8 hours after dilution  
• Monitoring 
o evidence of tumor response  
o peripheral blood counts  
o renal and hepatic function  
o signs and symptoms of myelosuppression 
• How Supplied 
o Intravenous Powder for Solution: 50 MG, 150 MG, 450 MG  
o Intravenous Solution: 10 MG/ML 
• Contraindications 
o hypersensitivity to cisplatin/platinum products or mannitol  
o severe myelosuppression/significant bleeding 
• Precautions 
o aluminum reacts with carboplatin to form an inactive precipitate; therefore, 
intravenous sets and needles containing aluminum which may come in contact 
with carboplatin should not be used  
o extravasation  
o patients over 65 years of age or those previously treated with cisplatin are at 
increased risk of developing carboplatin-induced peripheral neuropathy  
o prior aminoglycoside therapy may potentiate carboplatin-induced renal 
toxicity  
o renal impairment  
o use proper procedures for handling and disposal of chemotherapy 
• Adverse Events 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 28 
o COMMON 
 Gastrointestinal: Nausea and vomiting 
o SERIOUS 
 Endocrine metabolic: Electrolyte imbalance  
 Hematologic: Myelosuppression  
 Immunologic: Immune hypersensitivity reaction (2% to 9.2% )  
 Neurologic: Peripheral neuropathy  
 Ophthalmic: Visual disturbance (rare) 
 
1.3.3e Etoposide 
 
• Common Trade Names 
o Vepesid 
• Class 
o Antineoplastic Agent  
o Mitotic Inhibitor 
• FDA-Labeled Indications 
o Small cell carcinoma of lung, in combination therapy with other approved 
chemotherapeutic agents as first-line therapy 
o Testicular cancer, refractory (as combination therapy with other approved 
chemotherapeutic agents in patients who have already received appropriate 
surgical, chemotherapeutic, and radiotherapeutic therapy) 
o (Hodgkin lymphoma is a non-FDA labeled indication) 
• Dose Adjustments 
o compromised bone marrow reserve: adjust dose to account for 
myelosuppression caused by concurrent drugs, radiation therapy, or prior 
chemotherapy  
o hematologic: platelet count <50,000 cells/mm(3) or absolute neutrophil count 
(ANC) <500 cells/mm(3); withhold further therapy until blood counts have 
sufficiently recovered  
o renal impairment: an initial dose of 75% the recommended dose of etoposide 
for patients with a CrCl 15-50 mL/min 
• Administration 
o avoid rapid IV injection; administer over 30 to 60 minutes to avoid 
hypotension  
o dilute with D5W or NS to concentration of 0.2 to 0.4 mg/mL; MAXIMUM 
concentration 0.4 mg/mL (precipitation may occur)  


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 29 
o do not use undiluted in acrylic or ABS plastic because cracking and leaking 
may occur  
• Monitoring 
o evidence of tumor response  
o CBC; prior to and periodically during therapy  
• How Supplied 
o Intravenous Solution: 20 MG/ML 
• Contraindications 
o hypersensitivity to podophyllum 
• Precautions 
o administer etoposide over 30 to 60 minutes to reduce risk of hypotension  
o concomitant administration of drugs that inhibit phosphatase activities, high 
dose cyclosporin A  
o elderly patients (increased sensitivity to alopecia, gastrointestinal effects, 
infectious effects, nephrotoxicity, and myelosuppression); careful monitoring 
is warranted  
o extravasation (irritant)  
o impaired renal or hepatic function  
o low serum albumin may increase risk of etoposide toxicity  
o potential carcinogen  
o use proper procedures for handling and disposal of chemotherapy 
• Adverse Events 
o COMMON 
• Dermatologic: Alopecia  
• Endocrine metabolic: Shivering  
• Gastrointestinal: Diarrhea, Inflammatory disease of mucous 
membrane, Loss of appetite, Nausea, Vomiting  
• Neurologic: Asthenia  
• Other: Fever, Malaise 
o SERIOUS 
 Cardiovascular: Congestive heart failure, Myocardial infarction  
 Dermatologic: Stevens-Johnson syndrome, Toxic epidermal 
necrolysis  
 Hematologic: Acute leukemia (rare), Myelosuppression, Dose-
limiting (frequent)  


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 30 
 Hepatic: Hepatotoxicity  
 Immunologic: Immune hypersensitivity reaction (0.7-2%) 
 
1.4   Study Rationale and Selection of Drug Doses 
Please refer to section 1.3.1 for details. Selection of drug doses is based from our phase I trial 
of BICE as described in section 1.3.2c. 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 31 
2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objectives of this study are to: 
• 
To determine the objective response rate (ORR), partial remissions (PR), and complete 
remissions (CR) after 3 cycles of bortezomib plus ICE (BICE) versus ICE in patients with 
relapsed/refractory classical Hodgkin lymphoma (cHL). 
• 
To evaluate 2-year progression-free survival (PFS) in patients treated with 3 cycles of BICE 
versus ICE. 
2.2 Secondary Objectives 
The secondary objectives of this study are to: 
• 
To compare PET scan response after 3 cycles of BICE versus ICE chemotherapy. 
• 
To compare serum levels of tumor necrosis factor (TNF) proteins (APRIL, BLyS, sCD30, and 
CD40L) and CC thymus and activation-related cytokine (TARC) at baseline and after 3 cycles of 
BICE versus ICE chemotherapy. 
• 
To correlate baseline cytokine/chemokine levels with response to therapy. 
 
 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 32 
3 INVESTIGATIONAL PLAN 
3.1 Overall Design and Plan of the Study 
3.1.1   Pretreatment Evaluations 
3.1.1.a Within 28 to day 1 
 
1)  
Physical examination. 
2) 
Assess ECOG performance status and record the CTAE grade of any peripheral 
neuropathy symptoms. 
3) 
Review medical history and concomitant medications. 
4) 
Record the type and number of prior treatment regimens. 
5)  
Laboratory tests: CBC with differential, lytes, BUN, creatinine, bilirubin, AST, ALT, 
alkaline phosphatase, Hepatitis B and C serologies, and HIV serology. 
6)  
Imaging: (Within 61 days) Chest x-ray, CT scans of neck, chest, abdomen and pelvis;  
and PET/CT scan (within 61 days to day 1). 
7)  
Beta-hCG serum test for women of childbearing potential. 
8) 
If your doctor thinks it is needed, you will have a bone marrow biopsy to check the status 
of the disease. 
9) 
Echo/MUGA. 
 
3.1.1b Within 3 Days to day 1 of cycle 1 of BICE or ICE treatment 
1) 
Physical examination. 
2) 
Review concomitant medications. 
3) 
Laboratory tests: CBC with differential, lytes, BUN, creatinine, bilirubin, AST, ALT, and 
alkaline phosphatase. 
4)  
For patients who consent for optional procedure collect blood for serum evaluations of 
TNF and TARC proteins. 
 
3.1.2   Evaluations During Treatment 
 
1) 
On each day of BICE or ICE administration: CBC with differential, lytes, BUN, 
creatinine, AST, ALT, alkaline phosphatase, and bilirubin. 
2) 
While receiving BICE or ICE treatment until repeat staging has been completed: Weekly 
CBC with differential and electrolytes. 
3) 
Within 3 days of retreatment: CBC with differential, lytes, BUN, creatinine, AST, ALT, 
alkaline phosphatase, and bilirubin. 
 
End of Treatment Visit (After completing 3 cycles of Bice or ICE) 
Within 21 days (+ / - 7 days) from start of Cycle 3 or Early Termination: Physical examination, 
review of concomitant medications, and documentation of adverse events. Laboratory analysis 
with CBC with differential, lytes, BUN, creatinine, AST, ALT, alkaline phosphatase, and 
bilirubin. Repeat Chest x-ray, CT scans of neck, chest, abdomen, and pelvis, and PET/CT. 
Patients will have a bone marrow biopsy to check the status of the disease.  For patients who 
consent for optional procedure blood for serum evaluations of TNF and TARC proteins will be 
collected. 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 33 
 
 * For Outside Physician Participation During Treatment, please refer to section 8.8 
 
 
3.1.3  Duration of Treatment 
 
1) 
Autologous stem cell transplant candidates: Patients will receive a   
 
minimum of 3 cycles of BICE or ICE and a maximum of 6 cycles. Stem cell  
 
collection may be performed after cycle 3 or 4 of BICE or ICE. 
2) 
Non-transplant candidates: Patients can receive up to a maximum of 6 cycles of BICE or 
ICE if tolerated 
 
3.1.4  Follow-up Evaluations 
 
1)  
Patients who are eligible for autologous stem cell transplant will proceed on to this 
therapeutic intervention. 
2) 
All patients will undergo follow-up evaluations every 4 months for 2 years with: Physical 
exam, review of adverse events, laboratory analysis with CBC with differential, lytes, 
BUN, creatinine, AST, ALT, alkaline phosphatase, and bilirubin, and repeat imaging 
with chest x-ray and CT scans of neck, chest, abdomen and pelvis. 
 
 
Figure 2A: BICE and ICE Treatment Schema BICE: Bortezomib will be given on Day 1 and 4 at 
a dose of 1.5 mg/m2 and ICE on Days 1 to 3 with Neulasta given on Day 5 (While Neulasta is 
preferred, appropriate equivalent doses of filgrastim can be used). ICE: ICE on Days 1 to 3 with 
Neulasta given on Day 4.  Treatment will be repeated every 14 days if ANC > 1000 cells/mm3 
and platelets ≥ 90,000 cells/mm3. Treatment may be delayed by 14 days to allow for adequate 
count recovery. Patients will undergo weekly blood work with CBC with diff, lytes, BUN/Cr, 
and LFTs. Figure 2B: Determination of Response Evaluation of ORR and CR will be performed 
according to IWG 1999 response criteria (Cheson et al., 1999) with PET scans assessed as a 
secondary endpoint. CT and PET scans will be performed prior at enrollment and 21 days after 
completion of cycle 3 of treatment. Serum protein levels will be assessed at enrollment and on 
day of repeat imaging after cycle 3. 
 
A study flow chart is provided in section 0. 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 34 
3.2 Selection of Patients 
The maximum number of patients to be enrolled on this study is 50 (see section 5.1). 
Enrollment is defined as the first day of BICE versus ICE 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: 
 
1) 
Relapsed or refractory classical Hodgkin lymphoma 
2) 
Patients must have received a front-line standard anthracycline- 
 
 
 
containing regimen, such as ABVD, Stanford V, or BEACOPP. 
3) 
Bi-dimensionally measurable disease with at least 1 lesion ≥ 2.0 cm  
 
 
in a single dimension. 
4) 
Patients must meet the following required baseline laboratory data:  
 
 
 
a) absolute neutrophil count (ANC) ≥ 1,500/μL, b) platelet count ≥  
 
 
100,000/ μL, c) hemoglobin ≥ 8 g/dL, d) serum bilirubin < 2.0  
 
 
 
mg/dL, e) alkaline phosphatase < 2 x upper limits of normal (ULN),  
 
 
 
f) AST and ALT < 2 x ULN, g) serum creatinine ≤ 1.5 mg/dL.  
5) 
Eastern Cooperative Oncology Group (ECOG) performance status   
 
 
of less than or equal to 2 (see section 8.2).  
6) 
Age ≥ 16 years. 
7) 
Females of childbearing potential must have a negative serum beta-hCG pregnancy test 
and must agree to use 2 highly effective contraceptive methods (hormonal contraceptive, 
intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) 
during the study and for 3 months after completion of protocol treatment. Females of 
non-childbearing potential are those who are postmenopausal for greater than 1 year or 
whom have had a bilateral tubal ligation or hysterectomy. 
8) 
Males who have partners of childbearing potential must agree to   
 
 
use an effective contraceptive method during the study and for 3   
 
 
months after completion of protocol treatment. 
9) 
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. 
3.2.2  Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
 
1)  
Lymphocyte predominant Hodgkin lymphoma histology. 
2) 
More than one prior chemotherapy regimen. 
3) 
Prior autologous or allogeneic stem cell transplant. 
4) 
Presence of CNS involvement with Hodgkin lymphoma. 
5) 
Known HIV infection or AIDS. 
6) 
Active Hepatitis B or C infection or history of cirrhosis. 
7) 
Grade 2 or greater peripheral neuropathy within 14 days of   
 
 
 
enrollment. 
8) 
Hypersensitivity to boron or mannitol. 
9) 
Prior bortezomib therapy. 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 35 
10) 
Another primary malignancy (other than squamous cell and basal   
 
 
cell carcinoma of the skin, in situ carcinoma of the cervix, or  
 
 
 
 
squamous intraepithelial lesion on PAP smear, or treated   
 
 
 
prostate cancer with a stable PSA) for which the patient has not  
 
 
 
been disease-free for at least 3 years. 
11) 
Patients with congestive heart failure, Class III or IV (see section 8.4), by New York  
 
Heart Association (NYHA) criteria. 
12)  
Patients with a myocardial infarction 6 months prior to enrollment,  
 
 
 
uncontrolled angina, severe uncontrolled ventricular arrthymias, or  
 
 
 
ECG evidence of acute ischemia or active conduction system  
 
 
 
abnormalities. 
13) 
Patient with other medical or psychiatric illness that is likely to  
 
 
 
interfere with participation in this clinical study. 
14) 
Female subject that is pregnant or breast-feeding. 
15) 
Patient that has received other investigational drugs within 14 days  
 
 
 
of enrollment. 
16) 
Patients using concurrent therapy with corticosteroids at greater  
 
 
 
than or equal to 20 mg/day of prednisone equivalent. 
17) 
Patients with active systemic bacterial, viral, or fungal infections   
 
 
that have required IV antimicrobials within 4 weeks prior to protocol  
 
 
 
treatment. 
3.3 Study Treatments 
3.3.1 Clinical Trial Materials 
VELCADE (bortezomib) for Injection is a sterile lyophilized powder for reconstitution and is 
supplied in vials containing VELCADE and mannitol at a 1:10 ratio.  For example, vials 
containing 3.5 mg of VELCADE contain 35 mg of mannitol.   
Ifosfamide, MESNA, Carboplatin, and Etoposide are packaged and prepared per UT MD 
Anderson Cancer Center pharmacy’s standard operating procedures. 
3.3.2 Preparation, Handling, and Storage of Drugs 
Vials containing lyophilized VELCADE for Injection should be stored according to the label 
requirements.  For the United States, store at USP Controlled Room Temperature which is 25ºC 
(77ºF); excursions permitted from 15 to 30ºC (59 to 86ºF).  For Europe, do not store above 30ºC 
(86ºF).  To date, stability data indicate that the lyophilized drug product is stable for at least 18 
months when stored under the recommended conditions. Stability studies are ongoing, and 
Millennium Pharmaceuticals, Inc. will notify the investigator should this information be revised 
during the conduct of the study. 
VELCADE is cytotoxic.  As with all cytotoxic drugs, caution is required when preparing and 
handling VELCADE solutions.  Cytotoxic drugs should only be handled by staff specially 
trained in the safe handling of such preparations. The use of gloves and other appropriate 
protective clothing is recommended.  In case of skin contact, wash the affected area immediately 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 36 
and thoroughly with soap and water for at least 15 minutes.  If product contacts eye, immediately 
flush eye thoroughly with water for at least 15 minutes.  Always contact a physician after any 
form of body contact. All materials that have been used for preparation should be disposed of 
according to standard practices. A log must be kept of all disposed materials. 
Drug is available in sterile, single use vials containing 3.5 mg of VELCADE.  Each vial of 
VELCADE for Injection should be reconstituted under a laminar flow biological cabinet (hood) 
within eight hours before dosing with 3.5 mL of normal (0.9%) saline, Sodium Chloride 
Injection USP, so that the reconstituted solution contains VELCADE at a concentration of 
1 mg/mL.  Prior to reconstitution the vials should remain in the cartons to protect them from 
light.  Dissolution is completed in approximately 10 seconds.  The reconstituted solution is clear 
and colorless, with a final pH of 5 to 6.  Reconstituted VELCADE should be administered 
promptly and in no case more than 8 hours after reconstitution.  All materials that have been used 
for preparation should be disposed of according to standard practices.  A log must be kept of all 
disposed materials. 
Ifosfamide, MESNA, Carboplatin, and Etoposide are prepared, handled, and stored per UT MD 
Anderson Cancer Center pharmacy’s standard operating procedures. 
3.3.3 Drug Administration and Dosage Schedule 
Drug will be administered only to eligible patients under the supervision of the principal 
investigator or identified sub-investigator(s). Treatment will be delivered in the hospital under 
the supervision of the principal investigator or a sub-investigator.  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 0). For patients with a calculated BSA of ≥ 2.1 
m2 use of adjusted body weight for drug dosing (see section 8.3) can be considered to calculate 
an adjusted BSA.  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.  
  
The appropriate amount of VELCADE will be drawn from the injection vial and administered as 
an intravenous (IV) push over 5 seconds followed by a standard saline flush or through a running 
IV line.  Vials are for single use administration.   
 
3.3.3a Arm A: BICE Treatment 
 
Treatment will consist of bortezomib plus ICE (ifosfamide, carboplatin, etoposide) 
chemotherapy (BICE) (Table 3). 
 
Table 3: Arm A Treatment with BICE  
 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 37 
 
3.3.3b Arm B: ICE Treatment 
 
Treatment will consist of ICE (ifosfamide, carboplatin, etoposide) chemotherapy (Table 4).  
 
Table 4: Arm B Treatment with ICE  
 
Day 
Drug 
Dose Level 
Infusion Time 
1 
Ifosfamide + 
MESNA 
5 gm/m2 + 5 gm/m2
IV continuous 
infusion over 24 hrs 
2 
MESNA 
2 gm/m2 
IV continuous 
infusion over 12 
hours to start after 
the completion of 
the 24 hour 
continuous infusion 
of Ifosfamide and 
Mesna  
1 
Carboplatin 
Target AUC = 5 
mg/mL/min 
(Maximum dose of 
800 mg) 
IV over 1 hr 
1 through 3 
Etoposide 
100 mg/m2/day 
IV over 2 hrs daily 
x 3 doses 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 38 
3.3.4 
Dose Modification and Delay 
 
Before each drug dose, the patient will be evaluated for possible toxicities that may have 
occurred after the previous dose(s).  Toxicities are to be assessed according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE), Version 3.0 (see section 0).   
Table 5  
Management of Patients with VELCADE Related Peripheral Sensory or 
Motor Neuropathy at Retreatment 
Recommended Dose Modification at Retreatment for VELCADE Related 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 loss of function)  
*No action, continue VELCADE at 1.5 mg/m2/dose 
Grade 2 (interfering with  
function but not with activities of daily living)  
*Reduce VELCADE dose to 1.3 mg/m2/dose 
Grade 3 (interfering with activities of daily living) or Grade 4 
(Sensory neuropathy which is disabling or motor neuropathy 
that is life threatening or leads to paralysis)   
Discontinue treatment on clinical protocol  
Grading based on NCI Common Terminology Criteria CTCAE v3.0    
NCI Common Terminology Criteria website - http://ctep.info.nih.gov/reporting/ctc.html  
ADL = activities of daily living 
Note: If the VELCADE dose has been reduced to 1.3 mg/m2/dose during prior cycle secondary to these dose reduction guidelines 
then if patient has grade 2 or less peripheral neuropathy at retreatment the dose level should remain at 1.3 mg/m2/dose  
The neurotoxicity-directed questionnaire (see section 8.7) is an optional but useful tool for 
determining the presence and intensity of peripheral neuropathy from the patient’s perspective.  
Neuropathic symptoms are more prominent than abnormalities on the clinical examination.   
 
 
3.3.4a Cycles of treatment and retreatment criteria 
 
Patients will be eligible for retreatment every 14 days if below criteria are met: 
 
 
1) Laboratory criteria: a) absolute neutrophil count (ANC) ≥ 1,000/μL, b)   
 
 
platelet count ≥ 90,000/ μL,  c) serum bilirubin < 2.0  
 
 
 
 
 
mg/dL, e) alkaline phosphatase < 2 x upper limits of normal (ULN),  
 
 
 
f) AST and ALT < 2 x ULN, and g) serum creatinine ≤ 1.5 mg/dL.  
 
 
2) Clinical criteria: a) peripheral neuropathy of grade 2 or less, b) lack of a  
 
 
grade 3 or 4 non-hematologic, non-nephrologic, or non-hepatic toxicity  
 
 
 
that cannot be controlled by supportive care. 
 
Retreatment may be delayed a maximum of 14 days to allow for above criteria to be met.  
 
3.3.4b Dose modification/toxicity management 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 39 
A number of measures will be taken to ensure the safety of patients participating in this clinical 
treatment protocol. In the phase I (MDACC 2006-0527) no hematologic or non-hematologic 
dose limiting toxicities (DLT) were noted for bortezomib given at the maximum dose of 1.5 
mg/m2 on Days 1 and 4 in combination with standard ICE chemotherapy (see section 1.3.2c and 
Fanale et al., 2008).These include the patient eligibility criteria (see section 3.2) and scheduled 
monitoring. Patients enrolled in this study will be evaluated clinically with standard laboratory 
tests before and during their participation in this study (see section 3.1). Safety evaluations will 
consist of medical interviews, recording of adverse events, physical examinations, blood 
pressure, and laboratory measurements. Subjects will be evaluated for adverse events (all 
grades), serious adverse events, and adverse events requiring study drug interruption or 
discontinuation at each study visit for the duration of their participation in the study. 
 
1) Bortezomib: In the phase I (MDACC 2006-0527) no hematologic or non-hematologic 
dose limiting toxicities (DLT) were noted for bortezomib given at the maximum dose of 
1.5 mg/m2 on Days 1 and 4 chemotherapy (see section 1.3.2c and Fanale et al., 2008). 
Any patient who experiences a Common Terminology Criteria for Adverse Events v3.0 
(CTAE) of a grade 3 peripheral neuropathy that does not resolve to grade 2 peripheral 
neuropathy by time of retreatment, grade 4 peripheral neuropathy, or a grade 3 to 4 non-
hematologic toxicity that is attributed to bortezomib will be removed from the study. For 
patients who have grade 2 peripheral neuropathy at retreatment dose should be reduced to 
bortezomib 1.3 mg/m2 (see Table 5). Patients will need to meet laboratory criteria for 
retreatment (see section 3.3.4a). Patients who experience a grade 4 thrombocytopenia or 
neutropenia for greater than 2 weeks will be removed from the study. 
 
2) Ifosfamide, MESNA, Carboplatin, and Etoposide: Patients will need to meet 
laboratory and clinical criteria for initial treatment and retreatment (see section 3.3.4a). 
Dose adjustments can be considered based on judgment of clinician but laboratory 
criteria for initial treatment and retreatment should be met. 
 
3.3.5  
Treatment Assignment 
Patients will be assigned to treatment arms A (BICE) and B (ICE) following the adaptive 
Bayesian statistical design (see section 3.6.1). 
3.3.6 
Packaging and Labeling 
VELCADE will be supplied in vials as open-label stock.  Both the box label and vial label will 
fulfill all requirements specified by governing regulations.   
Ifosfamide, MESNA, Carboplatin, and Etoposide will be supplied via the UT MD Anderson 
Cancer Center pharmacy through standard operating procedures which fulfill all requirements as 
specified by governing regulations. 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 40 
3.3.7 
Concomitant Treatment 
Required Concurrent Therapy 
The following medications/supportive therapies are required during study participation, as 
applicable: 
1) Patients will receive Neulasta 6 mg subcutaneously 24 hours after completion of 
chemotherapy. While Neulasta is preferred, appropriate equivalent doses of filgrastim can 
be used. 
2) In addition, standard prophylactic antimicrobials or appropriate equivalent will be 
given with: a) ciprofloxacin 500 mg po bid, b) fluconazole 100 mg po daily, c) 
valcyclovir 500 mg po daily; all starting on day 5 for 10 days.  
3) The use of erythropoietin is allowed per standard  ASCO/ASH guidelines. 
 
Prohibited Concurrent Therapy 
1) Any investigational agent other than VELCADE. 
3.3.8 
Treatment Compliance 
All drug will be administered to eligible patients under the supervision of the investigator or 
identified sub-investigator(s).  The pharmacist will maintain records of drug receipt (if 
applicable), drug preparation, and dispensing, including the applicable lot numbers, patients’ 
height, body weight, and body surface area (see section 0), and total drug administered in 
milliliters and milligrams.  Any discrepancy between the calculated dose and dose administered 
and the reason for the discrepancy must be recorded in the source documents. 
 
3.4 Duration of Treatment and Patient Participation 
3.4.1 Duration of Treatment 
 
 
1) Autologous stem cell transplant candidates: Patients will receive a  
 
 
minimum of 3 cycles of BICE or ICE and a maximum of 6 cycles. Stem cell  
 
collection may be performed after cycle 3 or 4 of BICE or ICE. 
 
2) Non-transplant candidates: Patients can receive up to a maximum of 6 cycles of BICE 
or ICE if tolerated. 
 
3.4.2  Follow-up Evaluations 
 
1) Patients who are eligible for autologous stem cell transplant will proceed on to this 
therapeutic intervention. 
 
2) All patients will undergo follow-up evaluations every 4 months for 2 years with: 
Physical exam, laboratory analysis with CBC with differential, lytes, BUN, creatinine, 
AST, ALT, alkaline phosphatase, and bilirubin, and repeat imaging with chest x-ray and 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 41 
CT scans of neck, chest, abdomen and pelvis. 
3.5 Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
• Intercurrent illness 
• Occurrence of an unacceptable adverse event 
• A treatment cycle delay or VELCADE interruption of >2 weeks or missing three of four 
VELCADE doses within a treatment cycle because of toxicity 
• Patient request 
• Protocol violations 
• Non-compliance 
• Administrative reasons 
• Failure to return for follow-up 
• General or specific changes in the patient’s condition unacceptable for further treatment 
in the judgment of the investigator 
• Progressive disease at any time 
At the time of withdrawal, 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. 
3.6 Efficacy, Correlative studies, and Safety Measurements 
3.6.1 Efficacy Measurements 
Response rates for BICE and ICE treatment groups will be assessed by  
1999 IWG (CT alone) (Cheson et al., 1999) (Table 6) and compared to 2007 IWG (CT plus PET) 
(Cheson et al., 2007) (Table 7) criteria. 
  
Table 6: 1999 IWG Response Criteria 
Response Category 
Physical 
Examination 
Lymph Nodes/ 
Masses 
Bone Marrow 
Complete Remission 
(CR) 
Normal 
Normal 
Normal 
Partial Remission (PR) 
Normal 
Normal 
Positive 
Normal 
≥ 50% Decrease 
Irrelevant 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 42 
Decreasing Liver/ 
Spleen 
≥ 50% Decrease 
Irrelevant 
Stable Disease (SD) 
Less than a PR but not Relapse/ Progressive Disease 
Relapse/ Progressive 
Disease (PD) 
Enlarging Liver/ 
Spleen; New Sites 
New or Increased 
Reappearance 
 
Table 7: 2007 IWG Response Criteria 
Response 
Category 
Definition 
Nodal Masses 
Spleen; Liver 
Bone Marrow 
CR 
Disappearance of 
all evidence of 
disease 
a) FDG-avid or 
PET positive 
prior to therapy; 
mass of any size 
permitted if PET 
negative 
b) Variably 
FDG-avid or 
PET negative; 
regression to 
normal size on 
CT 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared 
on repeat biopsy; 
if indeterminate 
by morphology 
IHC should be 
negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
≥ 50% decrease 
in sum of the 
product of 
diameters (SPD) 
of up to the 6 
largest dominant 
masses; no 
increase in size 
of other nodes 
a) FDG-avid or 
PET positive 
prior to therapy; 
one of more PET 
positive at 
previously 
involved site 
b) Variably 
FDG-avid or 
PET negative, 
regression on CT 
≥ 50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or spleen 
Irrelevant if 
positive prior to 
therapy; cell type 
should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
a) FDG-avid or 
PET positive 
prior to therapy; 
PET positive at 
prior sites of 
 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 43 
disease and no 
new sites on CT 
or PET 
b) Variably 
FDG-avid or 
PET negative; no 
change in size of 
previous lesions 
on CT 
Relapsed or PD 
Any new lesion 
or increase by ≥ 
50% of 
previously 
involved sites 
from nadir 
a) Appearance of 
a new lesion(s) > 
1.5 cm in any 
axis, ≥ 50% 
increase in 
longest diameter 
of a previously 
identified node > 
1 cm in short 
axis 
b) Lesions PET 
positive if FDG-
avid lymphoma 
or PET positive 
prior to therapy 
> 50% increase 
from nadir in the 
SPD of any 
previous lesions 
New or recurrent 
involvement 
 
 
 
 
 
3.6.2 Correlative Studies (optional) 
For patients who consent for optional procedure blood for serum evaluations of TNF (APRIL, 
BLyS, sCD30, CD40L) and TARC proteins will be collected within 3 days of cycle 1 of  BICE 
or ICE treatment and after 3 cycles of BICE or ICE treatment at 21 days (+/- 7 days). 
3.6.3 Safety Measurements 
Safety evaluations will consist of medical interviews, recording of adverse events, physical 
examinations, blood pressure, and laboratory measurements. Subjects will be evaluated for 
adverse events (all grades), serious adverse events, and adverse events requiring study drug 
interruption or discontinuation at each study visit for the duration of their participation in the 
study. 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 44 
4 ADVERSE EVENTS 
4.1 Definitions 
4.1.1 Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the treatment.  
An adverse event can be any unfavorable and unintended sign (eg, including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the drug, whether 
or not it is considered to be drug related.  This includes any newly occurring event or previous 
condition that has increased in severity or frequency since the administration of drug. 
4.1.2 Serious Adverse Event Definition 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that: 
• Results in death. 
• Is life-threatening.  Life-threatening means that the patient was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered AEs if the illness or disease 
existed before the patient was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (eg, surgery performed earlier than planned). 
• Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a persons’ ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event.  An important medical event is an event that may not 
result in death, be life-threatening, or require hospitalization but may be considered an 
SAE when, based upon appropriate medical judgment, it may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in the definitions for SAEs.  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.   
 
Clarification should be made between the terms “serious” and “severe” since they ARE NOT 
synonymous.  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 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 are 
usually associated with events that pose a threat to a patient’s life or functioning.  A severe 
adverse event does not necessarily need to be considered serious.  For example, persistent nausea 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 45 
of several hours duration may be considered severe nausea but not 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. 
4.2 Procedures for AE and SAE Reporting 
Investigator-sponsor must report all (SAE) regardless of relationship with any study drug or 
expectedness to Millennium Pharmacovigilance (or designee) as soon as possible, but no later 
than 5 calendar days of the investigator-sponsor’s observation or awareness of the event.  All 
sub-investigators must report all SAEs to the investigator-sponsor so that the investigator-
sponsor can meet his/her foregoing reporting obligations to Millennium Pharmacovigilance.  
Investigator-sponsor must also provide Millennium Pharmacovigilance with a copy of all 
communications related to the Study or Drug with the applicable regulatory authority, including, 
but not limited to, telephone conversation logs, as soon as possible but no later than 5 calendar 
days of that communication.  
Millennium Pharmacovigilance will send to the investigator-sponsor a monthly listing of the 
SAE reports received for SAE verification.  Investigator-sponsor will be responsible for 
forwarding such reports to any sub-investigator(s) and providing any follow-up safety 
information requested by Millennium Pharmacovigilance.  
 
SAE Reporting Contact Information  
PPD, Inc. 
Safety and Medical Management 
Fax: +1 (888) 488-9697 
Hotline number (24/7): +1 (800) 201-8725 
 
For both serious and non-serious adverse events, the investigator or sub-investigator must 
determine both the intensity of the event and the relationship of the event to drug administration. 
 
Relationship to drug administration will be determined by the investigator or sub-investigator 
responding yes or no to the question: Is there a reasonable possibility that the adverse event is 
associated with the drug? 
Intensity for each adverse event, including any lab abnormality, will be determined by using the 
NCI CTCAE, version 3.0, as a guideline, wherever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html.  
 
4.3 Monitoring of Adverse Events and Period of Observation 
Adverse events, both serious and non-serious, and deaths that occur during the patient’s study 
participation will be recorded in the source documents.  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). 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 46 
 
4.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects she is pregnant while participating in this study, she 
must inform her treating physician immediately and permanently discontinue drug therapy.  All 
pregnancies and suspected pregnancies must also be reported to Millennium Pharmacovigilance 
(or designee, see section 4.2) immediately.    The pregnancy must be followed through outcome 
(i.e. delivery, still birth, miscarriage). 
 
If a female partner of a male subject becomes pregnant during the male subject’s participation in 
this study, Millennium Pharmacovigilance must be contacted immediately.  Every effort should 
be made to follow the pregnancy for the final pregnancy outcome. 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 47 
5   STATISTICAL PROCEDURES 
5.1  Bayesian Adaptive Algorithm 
The phase II part of this study is to compare ICE only and BICE in treating patients with 
classical Hodgkin lymphoma.  The primary outcome is complete remission.  The estimated 
accrual rate is 2 or 4 patients per month.   A maximum of 50 patients will be accrued.  Patients 
will be evaluated for response after 0.75 months after receiving treatment for 3 cycles (21 days 
per cycle).  The patients will be randomized between ICE and BICE arms using a Bayesian 
adaptive algorithm (Berry and Eick,, 1995).  In general, the trial will proceed as follows: The 
initial 20 patients will be randomized fairly with probability of 0.50 each between the two arms, 
so that the number of patients in each arm is equal at the start of the trial.  Thereafter, as the trial 
proceeds patients will be randomized to the two groups with unequal probabilities in favor of the 
treatment that, on average, yields better response rate.  Consequently, each successive patient is 
more likely to receive the treatment with a better response rate, on average.  The details of the 
adaptive randomization scheme are as follows: 
Denote the response rate at each of the two treatment arms by {π1, π2} (1 for ICE, 2 for BICE).  
Based on the currently available data, we assume the prior distribution for the response rate is π1 
~ Beta (0.5, 0.5) and π
2 ~ Beta (0.6, 0.4), respectively.  The resulting prior mean (95% credible 
interval) for ICE and BICE are 0.5(0.002, 0.99) and 0.6(0.007, 0.99), respective 
ely.  After the initial first 20 patients being randomized to two treatment groups with an equal 
probability, each new patient will be randomized to receive treatment i with probability 
ρi=prob(πi > πj, j ≠i| Data), i, j=1,2.  If one of these two randomization probabilities falls below 
0.025 then that arm will be dropped.  In addition, if prob(πi > 0.25|data) < 0.05, i.e. the data 
indicates that the response rate in that arm is highly unlikely to be larger than 0.25, then that arm 
will be dropped.  On the other hand, if one of the two randomization probabilities exceeds 0.975 
then the trial will be terminated and that treatment arm will be selected.  If the trial does not stop 
early and the maximum 50 patients are accrued, a treatment is selected as being “better” if the 
probability that one treatment’s response rate is larger than the other’s response rate exceeds 
0.95.   
Table 8 below summarizes operating characteristics of the design based on an accrual of 50 
patients, and shows the results when the number of patients accrued per month are 2. The 
number of patients treated (and evaluated) row is the average number of patients treated on a 
given arm under the given scenario.  The calculations were done from 1,000 simulations. 
 
Table 8: Operating Characteristics for the Adaptive Randomization When 2 Patients Are 
Accrued Per Month 
 
Treatment Arms 
 
ICE 
BICE 
True Prob( Complete 
Remission ) 
0.2 
0.3 
Average  # Patients Treated 
13.4 ( 2, 33 ) 
16.5 ( 1, 37 ) 
Pr(Selected) 
0.058 
0.375 
Pr(Selected Early) 
0.009 
0.08 
Pr(Dropped Early) 
0.491 
0.098 
Average Trial Length (months) 
14.9 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 48 
 
The trial will be conducted using a website developed in the Division of Quantitative Sciences at 
UT MD Anderson Cancer Center. Through the web interface, which is ideal for a multicenter 
trial, the users can randomize patients and update last evaluation date and current patient status. 
When a patient is randomized, the calculations are based on all available data entered into the 
website. The results of the randomization are displayed to the screen for the user to view. All 
data will be stored in a secure SQL server database.  In addition, safety monitoring will also be 
performed in conjunction with the MDACC Data Safety Monitoring Board (DSMB).   
 
5.2  Efficacy Analysis 
 
In addition, response rates based on 1999 IWG (Cheson et al., 1999) versus 2007 IWG (Cheson 
et al., 2007) criteria will also be summarized for each treatment group (see section 3.6.1). 
Response rate improvement by PET scan assessment will also be described for patients with PR 
based on IWG 1999 criteria but who by IWG 2007 criteria are found to be in CR because of PET 
scan negativity in residual masses. 
 
5.3 Correlative TNF and TARC Serum Protein Level Analysis 
 
Furthermore, serum levels of TNF proteins (APRIL, BLyS, sCD30, and CD40L) and TARC as 
determined at baseline compared to post-treatment with will be analyzed for both the BICE and 
ICE treatment groups by Mann-Whitney U test. Second, serum levels for each protein as 
determined at baseline compared to post-treatment will be analyzed for both the BICE and ICE 
treatment groups according to response rates as determined by IWG 1999 response criteria (CR, 
PR, SD, versus PD) by the Kruskal-Wallis test. Third, serum levels for each protein as 
determined at baseline compared to post-treatment will be analyzed for both the BICE and ICE 
treatment groups according to PET scan results (PET negative versus PET positive) at 
completion of therapy by the Kruskal-Wallis test. Significance will be set for p ≤ 0.05.  
 
 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 49 
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 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 50 
review and approval/favorable opinion for minor change(s) in ongoing studies that have the 
approval /favorable opinion of the IRB/IEC.  The investigator will submit all protocol 
modifications to 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 VELCADE 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: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient complete and/or evaluable data 
• Plans to modify, suspend or discontinue the development of the drug 
Should the study be closed prematurely, all study 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).   
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 51 
7    REFERENCES 
Abali H, Urun Y, Oksuzoglu B, et al. Comparison of ICE (ifosfamide-carboplatin-etoposide) 
versus DHAP (cytosine arabinoside-cisplatin-dexamethasone) as salvage chemotherapy in 
patients with relapsed or refractory lymphoma. Cancer Invest. 2008;26:401-406. 
 
Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD et al. Proteasome 
inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999; 59 
(11):2615-22. 
 
Annunziata C, Davis R, Demchenko Y, et al. Frequent engagement of the classical and 
alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer 
Cell. 2007;12:115-130. 
 
Ansell SM, Horwitz SM, Engert A, et al. Phase I/II Study of an Anti-CD30 Monoclonal 
Antibody (MDX-060) in Hodgkin's Lymphoma and Anaplastic Large-Cell Lymphoma 
10.1200/JCO.2006.07.8972. J Clin Oncol. 2007;25:2764-2769. 
 
Bartlett NL, Younes A, Carabasi MH, et al. A phase 1 multidose study of SGN-30 
immunotherapy in patients with refractory or recurrent CD30+ hematologic malignancies. Blood. 
2008;111:1848-1854. 
 
Berry, DA and Eick, SG. Adaptive assignment versus balanced randomization in clinical trials: 
A decision analysis. Statistics in Medicine. 1995.14:231-246. 
 
Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al. Criteria for evaluating 
disease response and progression in patients with multiple myeloma treated by high-dose therapy 
and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European 
Group for Blood and Marrow Transplant. Br J Haematol 1998; 102 (5):1115-23. 
 
Blum KA, Johnson JL, Niedzwiecki D, Cannellos GP, Cheson BD, Bartlett NL. A phase II study 
of bortezomib in relapsed Hodgkin lymphoma: Preliminary results of CALGB 50206. J Clin 
Oncol (Meeting Abstracts). 2006;24:7576-. 
 
Bossen C, Schneider P. BAFF, APRIL and their receptors: structure, function and signaling. 
Semin Immunol. 2006;18:263-275. 
 
Cheson BD, Horning SJ, Coiffier B, et al. Report of an International Workshop to Standardize 
Response Criteria for Non-Hodgkin's Lymphomas. J Clin Oncol. 1999;17:1244- 
 
Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for Malignant Lymphoma. 
J Clin Oncol. 2007;25:579-586. 
 
Cusack JC, Jr., Liu R, Houston M, Abendroth K, Elliott PJ, Adams J et al. Enhanced 
chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear 
factor-kappaB inhibition. Cancer Res 2001; 61 (9):3535-40. 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 52 
 
Davies AM, Lara PN, Lau DH, et al. The proteasome inhibitor, bortezomib, in combination with 
gemcitabine (Gem) and carboplatin (Carbo) in advanced non-small cell lung cancer (NSCLC): 
Final results of a phase I California Cancer Consortium study. ASCO Meeting Abstracts. 
2004;22:7106-. 
 
Endo T, Nishio M, Enzler T, et al. BAFF and APRIL support chronic lymphocytic leukemia B-
cell survival through activation of the canonical NF-{kappa}B pathway. Blood. 2007;109:703-
710. 
 
Fanale MA, Fayad LE, Pro B, et al. A Phase I Study of Bortezomib in Combination with ICE 
(BICE) in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma. ASH Annual 
Meeting Abstracts. 2008;112:3048-. 
 
Fanucchi MP, Fossella FV, Belt R, et al. Randomized phase II study of bortezomib alone and 
bortezomib in combination with docetaxel in previously treated advanced non-small-cell lung 
cancer. J Clin Oncol. 2006;24:5025-5033. 
 
Filmont JE, Gisselbrecht C, Cuenca X, et al. The impact of pre- and post-transplantation positron 
emission tomography using 18-fluorodeoxyglucose on poor-prognosis lymphoma patients 
undergoing autologous stem cell transplantation. Cancer. 2007;110:1361-1369. 
 
Forero-Torres A, Furman RR, Rosenblatt JD, et al. A humanized antibody against CD40 (SGN-
40) is well tolerated and active in non-Hodgkin's lymphoma (NHL): Results of a phase I study. J 
Clin Oncol (Meeting Abstracts). 2006;24:7534-. 
 
Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F et al. Randomized phase III 
trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung 
cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-
Small Cell Lung Cancer Study Group. J Clin Oncol 2000; 18 (12):2354-62. 
 
Fossella F. Docetaxel + Cisplatin (DC) and Docetaxel + Carboplatin (DCb) vs Vinorelbine + 
Cisplatin (VC) in chemotherapy-naïve patients with advanced and metastatic non-small cell lung 
cancer (NSCLC): Results of a multicenter, randomized phase III study. European Journal of 
Cancer, European Cancer Conference, ECCO 11, 2001; Lisbon, Portugal. 37(suppl 6):S154. 
Abstract 562  
 
Gallamini A, Hutchings M, Rigacci L, et al. Early interim 2-[18F]fluoro-2-deoxy-D-glucose 
positron emission tomography is prognostically superior to international prognostic score in 
advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J Clin Oncol. 
2007;25:3746-3752. 
 
Hamblett KJ, Barton J, Cerveny CG, et al. SGN-35, an Anti-CD30 Antibody-Drug Conjugate, 
Exhibits Potent Antitumor Activity for the Treatment of CD30+ Malignancies. ASH Annual 
Meeting Abstracts. 2005;106:610-. 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 53 
Heeschen C, Dimmeler S, Hamm CW, et al. Soluble CD40 Ligand in Acute Coronary 
Syndromes. N Engl J Med. 2003;348:1104-1111. 
 
Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J et al. The 
proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance 
in human multiple myeloma cells. Cancer Res 2001; 61 (7):3071-6. 
 
Hsu SJ, Esposito LA, Aukerman SL, Kantak S, Mirza AM. HCD122, an Antagonist Human 
Anti-CD40 Monoclonal Antibody, Inhibits Tumor Growth in Xenograft Models of Human 
Diffuse Large B-Cell Lymphoma, a Subset of Non-Hodgkins Lymphoma. ASH Annual Meeting 
Abstracts. 2006;108:2519-. 
 
Hutchings M, Loft A, Hansen M, et al. FDG-PET after two cycles of chemotherapy predicts 
treatment failure and progression-free survival in Hodgkin lymphoma. Blood. 2006;107:52-59. 
 
Jagannath S, Barlogie B, Berenson J et al. A Phase 2 study of two doses of bortezomib in 
relapsed or refractory myeloma. Br J Haematol 2004: 127:165-172 
 
Josting A, Franklin J, May M, et al. New Prognostic Score Based on Treatment Outcome of 
Patients With Relapsed Hodgkin's Lymphoma Registered in the Database of the German 
Hodgkin's Lymphoma Study Group. J Clin Oncol. 2002;20:221-230. 
 
LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N et al. Proteasome 
inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine 
model. Cancer Res 2002; 62 (17):4996-5000. 
 
Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ. Proteasome inhibition 
measurements: clinical application. Clin Chem 2000; 46 (5):673-83. 
 
McConkey DJ, Pettaway C, Elliott P, Adam J, Papandreou C, Herrmann JL et al. The 
proteasome as a new drug target in metastatic prostate cancer. 7th Annual Genitourinary 
Oncology Conference, 1999; Houston, TX. Abstract  
 
Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step comprehensive high-dose 
chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by 
intent to treat and development of a prognostic model. Blood. 2001;97:616-623. 
 
Nadali G, Tavecchia L, Zanolin E, et al. Serum Level of the Soluble Form of the CD30 Molecule 
Identifies Patients With Hodgkin's Disease at High Risk of Unfavorable Outcome. Blood. 
1998;91:3011-3016. 
 
Novak AJ, Grote DM, Stenson M, et al. Expression of BLyS and its receptors in B-cell non-
Hodgkin lymphoma: correlation with disease activity and patient outcome 
10.1182/blood-2004-02-0762. Blood. 2004;104:2247-2253. 
 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 54 
 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
 
Oki Y, Georgakis GV, Migone T-S, Kwak LW, Younes A. Prognostic significance of serum B-
lymphocyte stimulator level in Hodgkin's lymphoma. Haematologica. 2007;92:269-270. 
 
Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S et al. Phase I Trial 
of the Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic Malignancies. J 
Clin Oncol 2002; 20 (22):4420-7. 
 
Palumbo A, Ambrosini MT, Benevolo G, et al. Bortezomib, melphalan, prednisone, and 
thalidomide for relapsed multiple myeloma. Blood. 2007;109:2767-2772. 
 
Papandreou C, Daliani D, Millikan RE, Tu S, Pagliaro L, Adam J. Phase I Study of Intravenous 
(I.V.) Proteasome Inhibitor PS-341 in Patients (Pts) with Advanced Malignancies. Proc Am Soc 
Clin Oncol, 2001. Abstract 340  
 
Pink MM, Pien CS, Ona VO, Worland P, Adams J, Kauffman MG. PS-341 enhances 
chemotherapeutic effect in human xenograft models. Proc Am Assoc Cancer Res, 2002; San 
Francisco, CA. Abstract 787 
 
Richardson PG, Barlogie B, Berenson J et al. A Phase II study of Bortezomib in Relapsed, 
Refractory Myeloma. N Engl J Med 2003; 348:2609-2617 
 
Richardson PG, et al., Bortezomib or High-Dose Dexamethasone for Relapsed Multiple 
Myeloma. N Engl J Med 2005; 352:2487-98.  
 
Richardson et al, Bortezomib Continues to Demonstrate Superior Efficacy Compared With High-
Dose Dexamethasone in Relapsed Multiple Myeloma: Updated Results of the APEX Trial. 
Blood, 2005; 106: Abstract 2547. 
 
San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus Melphalan and Prednisone for 
Initial Treatment of Multiple Myeloma. N Engl J Med. 2008;359:906-917. 
 
Schot BW, Zijlstra JM, Sluiter WJ, et al. Early FDG-PET assessment in combination with 
clinical risk scores determines prognosis in recurring lymphoma. Blood. 2007;109:486-491. 
 
Seam P, Juweid ME, Cheson BD. The role of FDG-PET scans in patients with lymphoma. 
Blood. 2007;110:3507-3516. 
 
Steiner P, Neumeier H, Lightcap E, Sadis S, Pien C, Pink M et al. Adaptation of Human Tumor 
Cell Lines to PS-341. AACR-NCI-EORTC International Conference, 2001; Miami Beach, FL. 
Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139. Abstract  


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 55 
 
Strauss SJ, Maharaj L, Hoare S, et al. Bortezomib Therapy in Patients With Relapsed or 
Refractory Lymphoma: Potential Correlation of In Vitro Sensitivity and Tumor Necrosis Factor 
Alpha Response With Clinical Activity. J Clin Oncol. 2006;24:2105-2112. 
 
Svoboda J, Andreadis C, Elstrom R, et al. Prognostic value of FDG-PET scan imaging in 
lymphoma patients undergoing autologous stem cell transplantation. Bone Marrow Transplant. 
2006;38:211-216. 
 
Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-341 in 
cancer therapy. Clin Cancer Res 1999; 5 (9):2638-45. 
 
Trelle S, Sezer O, Naumann R, et al. Bortezomib Is Not Active in Patients with Relapsed 
Hodgkin's Lymphoma: Results of a Prematurely Closed Phase II Study. ASH Annual Meeting 
Abstracts. 2006;108:2477-. 
 
VELCADE (bortezomib) [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; 
2003. 
 
Wedgwood AR, Fanale MA, Fayad LE, et al. Rituximab + ABVD Improves Event-Free Survival 
(EFS) in Patients with Classical Hodgkin Lymphoma in All International Prognostic Score (IPS) 
Groups and in Patients Who Have PET Positive Disease after 2 3 Cycles of Therapy. ASH 
Annual Meeting Abstracts. 2007;110:215-. 
 
Weihrauch MR, Manzke O, Beyer M, et al. Elevated Serum Levels of CC Thymus and 
Activation-Related Chemokine (TARC) in Primary Hodgkin's Disease: Potential for a Prognostic 
Factor. Cancer Res. 2005;65:5516-5519. 
 
Yazbeck V, Georgakis GV, Wedgwood A, Younes A. Hodgkin's lymphoma: molecular targets 
and novel treatment strategies. Future Oncol. 2006;2:533-551. 
 
Younes A, Consoli U, Snell V, et al. CD30 ligand in lymphoma patients with CD30+ tumors. J 
Clin Oncol. 1997;15:3355-3362. 
 
Younes A, Pro B, Fayad L. Experience with bortezomib for the treatment of patients with 
relapsed classical Hodgkin lymphoma. Blood. 2006;107:1731-1732. 
 
Younes A, Pro B, Fanale M, et al. Isotype-Selective HDAC Inhibitor MGCD0103 Decreases 
Serum TARC Concentrations and Produces Clinical Responses in Heavily Pretreated Patients 
with Relapsed Classical Hodgkin Lymphoma (HL). ASH Annual Meeting Abstracts. 
2007;110:2566-. 
 
Zheng B, Georgakis GV, Li Y, et al. Induction of Cell Cycle Arrest and Apoptosis by the 
Proteasome Inhibitor PS-341 in Hodgkin Disease Cell Lines Is Independent of Inhibitor of 
Nuclear Factor-{kappa}B Mutations or Activation of the CD30, CD40, and RANK Receptors. 
Clin Cancer Res. 2004;10:3207-3215. 


VELCADE (bortezomib) for Injection 
 
Clinical Study Protocol 2008-0604 
Millennium Pharmaceuticals, Inc. 
 
12/18/2008 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
Page 56 
8 
APPENDICES 
 


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol 
 [#] 
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization] 
] 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 57 
8.1   Study Flow Chart 
Assessment  
Screening 
Screening 
Pre-
treatmen
t 
Cycle 1 
Inter-cycle 
Pre-
treatme
nt 
Cycle 2 
Inter-cycle 
Pre-
treatmen
t 
Cycle 3 
Inter-cycle 
 End of 
Treatmen
t (EOT) 
Follow-up 
 
 Within 
61 days to 
Day 1 
 Within 
28 days to 
Day 1 
  Within 
3 Days 
to Day 1 
of Cycle 
1 
Day 1 to 
Day 5 
Weekly 
  
Within 
3 Days 
to Day 
1 of 
Cycle 2 
Day 1 to 
Day 5 
Weekly 
  Within 
3 Days 
to Day 1 
of Cycle 
3 
Day 1 to 
Day 5 
Weekly 
Within 21 
days (+/- 
7 days) 
from start 
of Cycle 
3 or Early 
Terminati
on 
Every 4 
months 
for 2 
years 
Physical 
Exam 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
ECOG PS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Grade of 
Peripheral 
Neuropathy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Review 
Medical 
History 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Record  
Meds 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
CBC + diff 
 
X 
X 
Xc 
X 
X 
Xc 
X 
X 
Xc 
X 
X 
X 
Lytes 
 
X 
X 
Xc 
X 
X 
Xc 
X 
X 
Xc 
X 
X 
X 


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol 
 [#] 
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization] 
] 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 58 
BUN/Cr, 
LFTs 
 
X 
X 
Xc 
 
X 
Xc 
 
X 
Xc 
 
X 
X 
Hep B/C & 
HIV 
serologies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
CXR & CT 
scans 
 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
PET/CT 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
BmBx 
 
X 
 
 
 
 
 
 
 
 
 
Xe 
 
Echo 
 
X 
 
 
 
 
 
 
 
 
 
 
 
B-HCG 
 
Xa 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X  
X 
 
 
 
 
 
 
 
 
 
 
Optional 
serum 
collection 
 
 
Xb 
 
 
 
 
 
 
 
 
Xb 
 
ICE or 
BICE 
chemo 
 
 
 
 
Xd 
 
 
Xd 
 
 
Xd 
 
 
Neulasta 
 
 
 
Xd 
 
 
Xd 
 
 
Xd 
 
 
 
Review 
Adverse 
Events 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol 
 [#] 
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization] 
] 
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 59 
a Beta-hCG serum test will be done for women of childbearing potential (see section 3.2). 
b For patients who sign an optional consent blood will be collected for serum evaluations of  TNF proteins (APRIL, BLyS, sCD30, and CD40L) and CC thymus and activation-related 
cytokine (TARC). 
c CBC with differential, Lytes, BUN, creatinine, AST, ALT, alkaline phosphatase, and bilirubin will be assessed on each day of BICE (Days 1 through 4) or ICE (Days 1 through 3) 
administration. 
d ICE chemotherapy will be given on Days 1 through 3 with Neulasta given on Day 4 and BICE will be given on Days 1 through 4 with Neulasta on Day 5 (see section 3.3.3). 
e If the doctor thinks it is needed, the patient will  have a bone marrow biopsy to check the status of the disease at screening.  On Day 21 (+/- 7 days) of Cycle 3, the patient will have a bone 
marrow biopsy to check the status of the disease. 
 


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization]
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 60 
8.2  ECOG Performance Status Scale 
The following table presents the ECOG performance status scale (Oken et al., 1982): 
  
Points 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
 


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization]
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 61 
8.3  Body Surface Area and Creatinine Clearance Calculations 
Body surface area (BSA) should be calculated using a standard nomogram that yields the 
following results in meters squared (m2): 
 
 
 
 
 
 
 
 
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as follows: 
 
CrCl (ml/min) =  (140-age) (actual wt in kg)               
 
 
 
   72 x serum creatinine (mg/dl) 
For females use 85% of calculated CrCl value. 
Note: In markedly obese patients, the Cockroft-Gault formula will tend to overestimate the 
creatinine clearance. (Adipose tissue tends to contribute little creatinine requiring renal 
clearance.) 
 
Body Surface Area:  
BSA(m2): ( ( ht(cm) * wt(kg) ) / 3600 )1/2 
Ideal Body Weight For Drug Dosing: 
Males(kg): 50 + 2.3*(ht(in)-(60 in)) 
Females(kg): 45.5 + 2.3*(ht(in)-(60 in)) 
Adjusted Body Weight For Drug Dosing: 
ABW(kg): IBW(kg) + 0.4*(wt(kg)-IBW(kg))


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization]
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 62 
8.4  New York Heart Association Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease: 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
_______________________________ 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown 
& Co; 1994:253-256. 


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization]
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 63 
8.5  Declaration of Helsinki 
World Medical Association Declaration of Helsinki: 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by 
the 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, 
Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th 
WMA General Assembly, Somerset West, Republic of South Africa, October 1996 and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical 
research involving human subjects.  Medical research involving human subjects includes 
research on identifiable human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people.  The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my patient will be my first consideration," and the International Code 
of Medical Ethics declares that, "A physician shall act only in the patient's interest when 
providing medical care which might have the effect of weakening the physical and mental 
condition of the patient." 
4. Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
5. In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology 
and pathogenesis of disease.  Even the best proven prophylactic, diagnostic, and therapeutic 
methods must continuously be challenged through research for their effectiveness, 
efficiency, accessibility and quality. 
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human beings 
and protect their health and rights.  Some research populations are vulnerable and need 
special protection.  The particular needs of the economically and medically disadvantaged 
must be recognized.  Special attention is also required for those who cannot give or refuse 
consent for themselves, for those who may be subject to giving consent under duress, for 


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization]
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 64 
those who will not benefit personally from the research and for those for whom the research 
is combined with care. 
9. Research Investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
1. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
2. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation. 
3. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
4. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol.  This protocol should be submitted 
for consideration, comment, guidance, and where appropriate, approval to a specially 
appointed ethical review committee, which must be independent of the investigator, the 
sponsor or any other kind of undue influence.  This independent committee should be in 
conformity with the laws and regulations of the country in which the research experiment is 
performed.  The committee has the right to monitor ongoing trials.  The researcher has the 
obligation to provide monitoring information to the committee, especially any serious 
adverse events.  The researcher should also submit to the committee, for review, information 
regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and 
incentives for subjects. 
5. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in this 
Declaration. 
6. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  The 
responsibility for the human subject must always rest with a medically qualified person and 
never rest on the subject of the research, even though the subject has given consent. 
7. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others.  This does not preclude the participation of healthy volunteers in 
medical research.  The design of all studies should be publicly available. 
8. Physicians should abstain from engaging in research projects involving human subjects 


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization]
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 65 
unless they are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed.  Physicians should cease any investigation if the risks are found to 
outweigh the potential benefits or if there is conclusive proof of positive and beneficial 
results. 
9. Medical research involving human subjects should only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the subject.  This is especially 
important when the human subjects are healthy volunteers. 
10. Medical research is only justified if there is a reasonable likelihood that the populations in 
which the research is carried out stand to benefit from the results of the research. 
11. The subjects must be volunteers and informed participants in the research project. 
12. The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
patient's information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject. 
13. In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations 
of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail.  The subject should be informed of the right to abstain from participation in 
the study or to withdraw consent to participate at any time without reprisal.  After ensuring 
that the subject has understood the information, the physician should then obtain the 
subject's freely-given informed consent, preferably in writing.  If the consent cannot be 
obtained in writing, the non-written consent must be formally documented and witnessed. 
14. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or may 
consent under duress.  In that case the informed consent should be obtained by a well-
informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
15. For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law.  These 
groups should not be included in research unless the research is necessary to promote the 
health of the population represented and this research cannot instead be performed on legally 
competent persons. 
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition 
to the consent of the legally authorized representative. 
17. Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population.  The 


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization]
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 66 
specific reasons for involving research subjects with a condition that renders them unable to 
give informed consent should be stated in the experimental protocol for consideration and 
approval of the review committee.  The protocol should state that consent to remain in the 
research should be obtained as soon as possible from the individual or a legally authorized 
surrogate. 
18. Both authors and publishers have ethical obligations.  In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results.  Negative as 
well as positive results should be published or otherwise publicly available.  Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared in 
the publication.  Reports of experimentation not in accordance with the principles laid down 
in this Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
1. The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic or therapeutic value.  When 
medical research is combined with medical care, additional standards apply to protect the 
patients who are research subjects. 
2. The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods.  This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists. 
3. At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by the 
study. 
4. The physician should fully inform the patient which aspects of the care are related to the 
research.  The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship. 
5. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods 
do not exist or have been ineffective, the physician, with informed consent from the patient, 
must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in 
the physician's judgement it offers hope of saving life, re-establishing health or alleviating 
suffering.  Where possible, these measures should be made the object of research, designed 
to evaluate their safety and efficacy.  In all cases, new information should be recorded and, 
where appropriate, published.  The other relevant guidelines of this Declaration should be 
followed. 


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization]
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 67 
8.6  Common Terminology Criteria for Adverse Events Version 3.0 
http://ctep.cancer.gov/reporting/ctc.html  


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization]
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 68 
8.7  FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 
FACT/GOG-Neurotoxicity Questionnaire, Version 4.0 
By circling one (1) number per line, please indicate how true each statement has been for you 
during the past 7 days. 
ADDITIONAL CONCERNS 
Not 
at all 
A little
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
I have numbness or tingling in my hands………
0
1
2 
3 
4
I have numbness or tingling in my feet…………
0
1
2 
3 
4
I feel discomfort in my hands………………….
0
1
2 
3 
4
I feel discomfort in my feet……………………
0
1
2 
3 
4
I have joint pain or muscle cramps……………
0
1
2 
3 
4
I feel weak all over……………………………
0
1
2 
3 
4
I have trouble hearing…………………………
0
1
2 
3 
4
I get a ringing or buzzing in my ears…………
0
1
2 
3 
4
I have trouble buttoning buttons………………
0
1
2 
3 
4
I have trouble feeling the shape of small objects 
when they are in my hand………………………
0
1
2 
3 
4
I have trouble walking…………………………
0
1
2 
3 
4
 
 
____________________________ 
Sources:  Cella DF, Tulsky DS, Gray G, Sarafian B, Lloyd S, Linn E, et al.  The functional assessment of 
cancer therapy (FACT) scale:  development and validation of the general measure.  J Clin Oncol 
1993;11(3):570-79. 
 
 
 
 
 
 
 
 


VELCADE (bortezomib) for Injection 
DRAFT                                        Clinical Study Protocol
Millennium Pharmaceuticals, Inc. 
                                                   [Date of Finalization]
VELCADE IIS Protocol Template MAF 6.30.2010 F 
CONFIDENTIAL 
page 69 
8.8 
Outside Physician Participation During Treatment 
 
 
 
1 
MDACC Physician communication with the outside physician is required prior 
to the patient returning to the local physician. 
 
 
 
This will be documented in the patient record 
 
2 
A letter to the local physician will outline the patient's participation in the clinical 
trial and will request local physician agreement to supervise the patient's care  
 
3 
Protocol required evaluations outside MDACC will be documented by telephone, 
fax or e-mail.  Fax and/or e-mail will be dated and signed by the MDACC 
physician, indicating that they have reviewed it. 
 
4 
Changes in drug dose and/or schedule must be discussed with and approved by 
the MDACC physician investigator, or their representative prior to initiation, and 
will be documented in the patient record. 
 
5 
A copy of the informed consent, protocol abstract, treatment schema and 
evaluation during treatment will be provided to the local physician. 
 
6 
Documentation to be provided by the local physician will include drug 
administration records, progress notes, reports of protocol required laboratory 
and diagnostic studies and documentation of any hospitalizations. 
 
7 
The home physician will be requested to report to the MDACC  
physician investigator all life threatening events within 24 hours of documented 
occurrence. 
 
8 
             Patients will return to MDACC after 3 cycles for evaluation. 
 
9 
Patients randomized to the ICE alone treatment group will be allowed to receive 
ICE with their local MD or at MDACC. For those randomized to the BICE 
group, they will be receive BICE at MDACC.