Conditions: Chronic Kidney Disease IgA Nephropathy
Keywords: Chronic kidney disease IgA nephropathy Velcade® Proteinuria Bortezomib Proteasome inhibitor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
The primary objective of this study is to investigate the ability of Velcade® (bortezomib) to induce complete or partial remission in patients with severe IgA nephropathy.

The secondary objectives are to assess clinical outcomes relating to safety and efficacy, such as infection, malignancy, preservation of renal function, partial responders, relapse rate, and to study mechanistic assays to predict remission.

Detailed description:
This exploratory single center, open-label, single treatment group assignment, safety and efficacy study will enroll 15 patients with severe IgA nephropathy. Subjects will receive 1 cycle of Velcade® to induce clinical remission. Follow-up visits will occur monthly for a year.

For this pilot study, the proportion of patients with clinical remission or partial response will be analyzed.

Arms:
arm 1: Patients with greater than 1gm of proteinuria per day will receive Velcade®.

Interventions: intervention 1: Bortezomib (Velcade®)
Intervention descriptions: intervention 1: Velcade® at 1.3 mg/m2, on days 1, 4, 8 and 11 (=1 cycle).

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
INVESTIGATOR INITIATED STUDY PROTOCOL 
 
 
Investigator: 
 
Choli Hartono, MD 
505 East 70th Street  
HT 226 
New York, NY 10021 
Telephone:  212-746-9708 
Fax: 212-746-8300 
 
Protocol Number: 
X05320 
 
 
Protocol Title: 
VELCADE® Therapy for Severe IgA Nephropathy 
 
 
 
Protocol Version: 
1.6 
 
 
Date of Protocol: 
11/28/11 
 
 
*VELCADE is the exclusive trademark of Millennium Pharmaceuticals, Inc., registered in the 
United States and internationally. 
 The Rogosin Institute 


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INVESTIGATOR SIGNATURE PAGE 
 
 
 
INVESTIGATOR STATEMENT 
 
 
 
I have read the protocol, including all appendices and in its latest version. I will conduct 
this study as outlined herein and will make a reasonable effort to complete the study within 
the time designated. 
 
As the principal investigator, I will conduct the trial in accordance with the guidelines of 
Good Clinical Practice (GCP), including the archiving of essential documents, the 
Declaration of Helsinki, any applicable local health authority requirements, and 
Institutional Review Board (IRB) requirements. 
 
 
 
Choli Hartono, MD 
__________________________________ 
Principal Investigator Name (Printed) 
 
 
 
 
__________________________________ 
Principal Investigator Signature 
 
 
The Rogosin Institute 
11/28/11 
__________________________________  
 
 
_________________ 
Institution 
 
 
 
 
 
 
 
Signature Date 
 
 
 
 
 
 


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PROTOCOL SUMMARY 
Title: VELCADE® Therapy for Severe IgA Nephropathy 
 
Objectives 
The primary objective of this study is to investigate the safety and ability of VELCADE to induce 
complete or partial remission in subjects with severe IgA nephropathy and risk factors for 
progression of disease. 
The secondary objectives of this study are to assess clinical outcomes relating to safety and 
efficacy, such as infection, malignancy, preservation of renal function, partial responders, relapse 
rate, and reduction in the requirement of anti-hypertensive drugs; and to study mechanistic 
assays to predict remission. 
Subject population 
Each subject must meet all of the following inclusion criteria to be enrolled in the study: 
1. Male or female, 18 years of age or older. 
2. Subject is capable of understanding the purposes and risks of the study, is willing to 
participate in and comply with the study, and can give 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. Female subject is either post-menopausal or surgically sterilized or willing to use an 
acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, 
diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of 
the study. 
4. Male subject agrees to use an acceptable method for contraception for the duration of the 
study. 
5. Subjects must have biopsy proven severe IgA nephropathy. 
6. Within 14 days before enrollment, creatinine clearance as measured by MDRD formula 
must be greater or equal to 30 cc/min/1.73 m2. 
7. Prior to enrollment, quantified proteinuria (via 24 hr urine collection or spot urine protein 
and creatinine ratio) must be greater or equal to 1000 mg.  
8. Unless contraindicated subject must be on stable doses of ACEI and/or ARB and/or renin 
inhibitor for at least 4 weeks prior to screening. 
 
Subjects meeting any of the following exclusion criteria will not be enrolled in the study: 
1. Subject has a platelet count of less than 30× 109/L within 14 days before enrollment. 
2. Subject has an absolute neutrophil count of less than 1.0 × 109/L within 14 days before 
enrollment. 
3. Subject has ≥Grade 2 peripheral neuropathy within 14 days before enrollment. 
4. Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure (see section 8.3), uncontrolled angina, 


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severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities. Prior to study entry, any ECG 
abnormality at screening has to be documented by the investigator as not medically 
relevant. 
5. Subject has hypersensitivity to VELCADE, boron or mannitol. 
6. Female subject is pregnant or breast-feeding.  Confirmation that the subject is not 
pregnant must be established by a negative serum β-human chorionic gonadotropin (β-
hCG) pregnancy test result obtained during screening.  Pregnancy testing is not required 
for post-menopausal or surgically sterilized women. 
7. Subject has received other investigational drugs within 14 days before enrollment. 
8. Serious medical conditions and infections (including HIV, HCV, HBV) or psychiatric 
illness likely to interfere with participation in this clinical study, as determined by review 
of the medical history. 
9. Diagnosed or treated for another malignancy within 3 years of enrollment, with the 
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of 
the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. 
10. Subject has total bilirubin greater than 1.5 x upper limit of normal. 
 
Number of subjects 
10 adult subjects with IgA nephropathy. 
 
Study design and methodology 
This exploratory single center, open-label, single treatment group assignment, safety and efficacy 
study will enroll 10 subjects with severe IgA nephropathy.  Subjects will receive 4 doses of 
VELCADE (1 cycle) to induce clinical remission.  Non-responders after a 4-week observation 
period will receive a second successive cycle of VELCADE. 
Treatments administered 
Subjects will receive 4 doses of VELCADE at 1.3 mg/m2 on days 1, 4, 8, and 11 (1 cycle).  Non-
responders will receive a second cycle at similar dosages.  Subjects will receive acyclovir 
prophylaxis. 
Efficacy data collected 
The following evaluations will be conducted to assess the efficacy of VELCADE: 
1) Quantification of urinary protein. 
2) Blood pressure monitoring. 
3) Measurement of serum creatinine. 
4) Urinalysis. 
Safety data collected 
The following evaluations will be conducted to assess the safety of VELCADE: 
1) Monitoring of CBC. 
2) Clinical follow-up for infections and malignancy. 
Statistical procedures 
For this pilot study, proportion of subjects with clinical remission or partial response will be 
analyzed. 


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TABLE OF CONTENTS 
1 
INTRODUCTION AND STUDY RATIONALE..............................................................9 
1.1 
Overview of the Disease ........................................................................................9 
1.2 
VELCADE 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..................................................................................13 
1.2.6 Potential Risks of VELCADE..................................................................14 
1.3 
Study rationale and selection of drug doses.........................................................19 
2 
STUDY OBJECTIVES....................................................................................................21 
2.1 
Primary Objective ................................................................................................21 
2.2 
Secondary Objectives...........................................................................................21 
3 
INVESTIGATIONAL PLAN..........................................................................................22 
3.1 
Overall Design and Plan of the Study..................................................................22 
3.2 
Selection of Subjects............................................................................................23 
3.2.1 Inclusion Criteria......................................................................................23 
3.2.2 Exclusion Criteria ....................................................................................23 
3.3 
Study Treatments .................................................................................................24 
3.3.1 Clinical Trial Materials ............................................................................24 
3.3.2 Preparation, Handling, and Storage of Drugs ..........................................24 
3.3.3 Dose Modification and Delay ..................................................................25 
3.3.4  Treatment Assignment………………………………….……………… 28 
3.3.5     Blinding, Packaging, and Labeling………………………...…………..28 
3.3.6 Concomitant Treatment............................................................................28 
 
3.3.7    Treatment Compliance.............................................................................28 
           3.4 
Duration of Treatment and Subject Participation ................................................29 
3.5 
Termination of Treatment and/or Study Participation .........................................29 
3.6 
Efficacy , Pharmacodynamic/Pharmacogenomic/Correlative studies, and 
Safety Measurements ...........................................................................................30 
3.6.1 Efficacy Measurements............................................................................30 
3.6.2 Safety Measurements ...............................................................................30 
4 
ADVERSE EVENTS.......................................................................................................31 
4.1 
Definitions............................................................................................................31 
4.1.1 Adverse Event Definition.........................................................................31 
4.1.2 Serious Adverse Event Definition............................................................31 
4.2 
Procedures for AE and SAE Reporting................................................................32 
4.3 
Monitoring of Adverse Events and Period of Observation..................................32 
4.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events..33 
5 
STATISTICAL PROCEDURES .....................................................................................34 
5.1 
Sample Size Estimation .......................................................................................34 
5.2 
Randomization and Stratification.........................................................................34 


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5.3 
Populations for Analysis ......................................................................................34 
5.4 
Procedures for Handling Missing, Unused, and Spurious Data...........................34 
5.5 
Statistical Methods...............................................................................................34 
5.5.1 Baseline Comparisons..............................................................................34 
5.5.2 Efficacy Analysis .....................................................................................34 
5.5.3 Safety Analysis ........................................................................................35 
 
 
5.5.4 Correlative Studies……………………………………………………...35 
5.6 
Data monitoring ...................................................................................................35 
5.7 
Procedures for Reporting Deviations to Original Statistical Analysis Plan.........35 
6 
ADMINISTRATIVE REQUIREMENTS........................................................................36 
6.1 
Good Clinical Practice .........................................................................................36 
6.2 
Ethical Considerations .........................................................................................36 
6.3 
Subject Information and Informed Consent.........................................................36 
6.4 
Subject Confidentiality ........................................................................................36 
6.5 
Protocol Compliance............................................................................................37 
6.6 
On-site Audits ......................................................................................................37 
6.7 
Drug Accountability.............................................................................................37 
6.8 
Premature Closure of the Study ...........................................................................37 
6.9 
Record Retention..................................................................................................38 
7 
REFERENCES.................................................................................................................39 
8 
APPENDICES .................................................................................................................42 
8.1 
Study Flow Chart .................................................................................................43 
8.2 
Body Surface Area and Creatinine Clearance Calculations.................................44 
8.3 
New York Heart Association Classification of Cardiac Disease.........................45 
8.4 
Declaration of Helsinki…………………………………………………………46 
8.5 
Common Terminology Criteria for Adverse Events Version 3.0 ........................50 
8.6 
FACT/GOG-Neurotoxicity Questionnaire, Version 4.0......................................50 
 
 


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ABBREVIATIONS LIST 
 
Abbreviation 
Definition 
°C 
degrees Celsius 
µM 
micromolar 
20S 
20S proteasome subunit 
ACEI 
angiotensin converting enzyme inhibitor 
AE 
adverse event 
ANC 
absolute neutrophil count 
ARB 
angiotensin receptor blockade 
Bc1-2 
B-cell lymphoma-2; a gene that inhibits apoptosis 
BSA 
body surface area 
CAM 
cell adhesion molecules  
cm 
centimeter 
CR 
Complete Response 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CV 
cardiovascular 
dL 
deciliter 
DLT 
Dose Limiting Toxicity 
DNA 
deoxyribonucleic acid 
FDA 
Food and Drug Administration 
EBMT 
European Group for Blood and Marrow Transplant 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GI 
gastrointestinal 
ht 
height 
IκB 
I kappa B kinase; cytokine response kinase that activates 
transcription factor NF-kappa b at serine 32 and 36 
ICAM-1 
intercellular adhesion molecule 1 
ICH 
International Conference on Harmonisation 
IL-6 
Interleukin-6 
iPs 
immunoproteasomes 


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Abbreviation 
Definition 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
intravenous 
IκBα 
I kappa B alpha-associated protein kinase 
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 
nM 
nanomole 
p21 
p21(ras) farnesyl-protein transferase 
p27 
cyclin-dependent kinase inhibitor 
p53 
tumor suppressor protein with molecular weight of 53 kDa 
PBMC 
peripheral blood mononuclear cell 
pIgA1 
polymeric immunoglobulin A1 
PK 
pharmacokinetics 
SAE 
serious adverse event 
US 
United States 
USP 
United States Pharmacopeia 
VCAM-1 
vascular cell adhesion molecule 1 
w/w 
weight-to-weight ratio 
wt 
weight 


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1 INTRODUCTION AND STUDY RATIONALE 
1.1 Overview of the Disease 
IgA nephropathy is the most common glomerular disease in the world.  Retrospective studies of 
affected patients reveal that the prognosis is highly variable with actuarial renal survival at 10 
years varying from 57% to 85% (D’Amico 2000).  The natural history of the disease is not 
benign with 60% of patients developing advance chronic or end-stage renal disease by 20 years 
(Samuels et al., 2004).   
 
There is no good animal model for IgA nephropathy.  In the 40 years since it was first 
characterized (Berger et al., 1968), understanding the pathogenesis and causation has been a 
challenging process.  Studies to date suggest that the pathogenesis is the deposition of abnormal 
polymeric IgA1 (pIgA1) immunoglobulins in the mesangium of kidney glomeruli causing an 
inflammatory immune response.  Pathogenic pIgA1s in patients with IgA nephropathy have 
abnormal O-galactosylation at the hinge region.  The aberrant pIgA1s have a propensity to form 
immune complexes and accumulate in the kidney mesangium.  There is evidence of increased 
plasma cells secreting altered pIgA1 in the bone marrow and tonsils of subjects with IgA 
nephropathy (Barratt et al., 2005).  Serum IgA level is elevated in up to 50% of patients at some 
point in the course of the disease.   
 
Transcription factor nuclear factor-κB (NF-κB) mediates the inflammatory immune response 
(cytokines, growth factors, and adhesion molecules) to abnormal pIgA1 deposition in the kidney 
mesangium.  Expression of NF-κB in kidney glomeruli and the interstitium correlated with 
progressive kidney tissue injury (Ashizawa et al., 2003). 
 
In vitro production of IL-6 by kidney mesangial and tubular cells can be stimulated by exposure 
to serum of subjects with IgA nephropathy (Wada et al., 2003).  Urinary IL-6 levels in subjects 
with progressive disease were significantly higher than stable subjects suggesting that elevated 
urinary IL-6 levels could be used to prognosticate disease (Harada et al., 2002). 
 
A switch to immunoproteasomes (iPS) was detected in peripheral blood mononuclear cells 
(PBMCs) of patients with IgA nephropathy and significant proteinuria.  Specifically, the switch 
to iPS of the chymotrypsin-like catalytic subunits (LMP7/β5) was significantly higher in IgA 
subjects not in clinical remission (Coppo et al., 2009).   
 
The risk for progression to end-stage renal disease is highest in patients with the following risk  
factors: elevated serum creatinine at presentation, significant proteinuria (greater than 1gm/day), 
hypertension, and persistent microhematuria (Goto et al., 2009; Mackinnon et al., 2008; Reich et 
al., 2007).  An international consensus report also proposed pathological features (mesangial 
hypercellularity, tubular atrophy/interstitial fibrosis, segmental glomerulosclerosis) that could 
prognosticate renal survival (Cattran et al., 2009).     
 


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Optimal therapy for the high-risk group to slow the deterioration of kidney function is ill defined.  
The pathogenesis of the disease has to be further investigated but initial events eliciting abnormal 
pIgA1 deposition in the kidney lead to an inflammatory response, which provides a rationale for 
immunomodulatory therapy (Floege et al., 2008).  Immunosuppressive medications such as 
azathioprine, corticosteroids, cyclophosphamide, and mycophenolate mofetil have been 
investigated as possible treatment for aggressive IgA kidney disease.  A clinical trial is ongoing 
for a B cell modulating drug (anti-CD20 monoclonal antibody) as a possible therapeutic agent 
for high-risk individuals.  There is no consensus on the use of immunomodulatory agents for 
severe IgA nephropathy.  Corticosteroid therapy had the most promise in a meta-analysis of 
randomized controlled trials (Samuels et al., 2004).  However, prolonged corticosteroid therapy 
has serious side effects including osteoporosis, hyperglycemia, significant weight gain, 
hypertension, and major infections. 
 
In this pilot study, we aim to investigate the effect of VELCADE in subjects with severe IgA 
nephropathy.  VELCADE is a proteasome inhibitor and potentially has activity against non-
cancerous plasma cells (Perry et al., 2008).  VELCADE may abrogate the production of 
abnormal pIgA1 in IgA nephropathy.  VELCADE may mitigate the expression of NF-κB in the 
kidney and reduce the inflammatory response to abnormal pIgA1 deposition.  Finally, 
VELCADE may interfere with the upregulation of iPS and promote clinical remission in severe 
IgA nephropathy.  
 
1.2 VELCADE for Injection 
1.2.1 Scientific Background 
VELCADE 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 who have received at least 
one prior therapy. 
  
By inhibiting a single molecular target, the proteasome, VELCADE affects multiple signaling 
pathways.  The anti-neoplastic effect of VELCADE 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 VELCADE 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.  VELCADE has a novel pattern of cytotoxicity in National Cancer Institute (NCI) in vitro 
and in vivo assays (Adams et al., 1999).  In addition, VELCADE 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, VELCADE induces apoptosis in cells that over express bcl-2, a 


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genetic trait that confers unregulated growth and resistance to conventional chemotherapeutics 
(McConkey et al., 1999). 
 
VELCADE 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). 
1.2.2 Nonclinical Pharmacology 
Pharmacokinetic (PK) and pharmacodynamic studies were conducted in the rat and cynomolgus 
monkey.  Upon intravenous (IV) bolus administration, VELCADE displays a rapid distribution 
phase (t½α <10 minutes) followed by a longer elimination phase (t½β 5–15 hours).  VELCADE 
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 VELCADE 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 
VELCADE 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 VELCADE.  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 VELCADE 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 VELCADE 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 VELCADE is similar across species, and target organs of 
toxicity in animals have been largely predictive of human toxicity.  The toxicity of VELCADE in 
animals is characterized by a steep dose-response with mortality seen at dosages above the MTD.  


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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 VELCADE on the CV system have been extensively characterized and have 
demonstrated that indirect effects on CV function occur only at acutely lethal dosages and are 
abrogated by routine supportive care. 
 
Additional detailed information regarding the nonclinical pharmacology and toxicology of 
VELCADE may be found in the Investigator’s Brochure. 
1.2.4 Clinical Pharmacokinetics and Pharmacodynamics 
The clinical pharmacology characterization of VELCADE 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. 
 
VELCADE 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 VELCADE were 57 and 112 ng/mL, respectively in 11 subjects 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 VELCADE upon multiple dosing ranged from 40 to 193 hours.   
 
VELCADE 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. 
 


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The relationship between VELCADE 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 VELCADE 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 VELCADE 
concentrations. 
1.2.5 Clinical Experience in Oncology 
It is estimated that more than 100,000 patients have been treated with VELCADE, including 
subjects treated through Millennium-sponsored clinical trials, Investigator-Initiated Studies, the 
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 1 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 subjects 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 dose-limiting toxicities (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 
subjects 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.   
 
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was designed to determine whether VELCADE provided benefit (time to progression [TTP], 
response rate, and survival) to subjects 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 subjects were enrolled and 663 subjects received study drug (VELCADE: 331; 
dexamethasone: 332).  Subjects 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. Subjects 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 
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 subjects 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 subjects on the VELCADE arm vs. subjects 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 subjects 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 subjects on the 
VELCADE arm vs. subjects 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 
To date, more than 100,000 patients have been treated with VELCADE in both clinical trials 
investigating its use in hematological malignancies and solid tumors, and in patients who were 
treated with commercially available VELCADE. 
 


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


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Table 1-1  Known Anticipated Risks of VELCADE by MedDRA System Organ Class, 
Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Infections and Infestations 
Very common  
Upper respiratory tract infection, nasopharyngitis, , 
pneumonia*, Herpes zoster* 
Common  
Lower respiratory tract infection*,  sinusitis, pharyngitis, 
oral candidiasis, urinary tract infection*,, 
sepsis*,bactaeremia*, cellulitis*,, Herpes simplex, 
bronchitis, gastroenteritis* 
Uncommon 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung infection*, 
infusion site cellulitis, catheter site cellulitis, infusion 
site infection,  urosepsis*, aspergillosis*, tinea infection, 
Herpes zoster ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic±, varicella, empyema±, 
fungal oesophagitis± 
Injury, Poisoning, and Procedural Complications  
 
 
Uncommon 
Subdural haematoma 
Investigations 
Common  
Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, 
blood alkaline phosphatase increased, liver function test 
abnormal, blood creatinine increased* 
Uncommon 
Gamma-glutamyltransferase (GGT) increased, oxygen 
saturation decreased*, blood albumin decreased, ejection 
fraction decreased* 
Metabolism and Nutritional Disorders 
 
 
Very common  
Decreased appetite, anorexia, dehydration* 
Common  
Hyperglycaemia, hypoglycaemia, hyponatraemia, 
hypokalaemia, hypercalcaemia* 
Musculoskeletal and Connective Tissue Disorders 
Very common  
Bone pain, myalgia, arthralgia 
Uncommon 
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon 
Tumor lysis syndrome* 
Nervous System Disorders 
Most common 
Peripheral neuropathy (including all preferred terms 
under the MedDRA high-level term peripheral 
neuropathy NEC) 
Very common  
Paresthesia, dizziness excluding vertigo; headache 
Common  
Polyneuropathy, syncope, dysesthesia, dysgeusia, 
postherpetic neuralgia 
Uncommon 
Convulsions, loss of consciousness, ageusia, 
encephalopathy, paralysis*, autonomic neuropathy, 
reversible posterior leukoencephalopathy syndrome± 
 
 
 


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Table 1-1  Known Anticipated Risks of VELCADE by MedDRA System Organ Class, 
Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Psychiatric Disorders 
Very common 
Anxiety, insomnia  
Common 
Confusional state 
Uncommon 
Delirium 
Renal and Urinary Disorders 
Common 
Renal impairment*, renal failure*, haematuria 
Uncommon 
Micturition disorder 
Respiratory, Thoracic, and Mediastinal Disorders 
Very common 
Cough, dyspnoea  
Common 
Epistaxis, dyspnoea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary oedema* 
Uncommon 
Hemoptysis*, acute respiratory distress syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar haemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, pleuritic 
pain 
Skin and Subcutaneous Tissue Disorders 
Very common 
Rash 
Common 
Rash pruritic, rash erythematous, urticaria, petechiae 
Uncommon 
Cutaneous vasculitis, leukocytoclastic vasculitis± 
Vascular Disorders 
 
 
Common 
Hypotension*, Orthostatic hypotension 
Uncommon 
Cerebral haemorrhage* 
Most common = ≥ 30%, Very common = 10% to 29%, Common=1% to 9%, Uncommon= < 1%, 
* Fatal outcomes have been reported. 
± Indicates a Preferred term not listed in the source table, however the event is deemed medically important 
and so is included. 
Source:  VELCADE Investigator’s Brochure, Version 12 
 


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Table 1-2    
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 
     Septic Shock 
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 diseaseb  
 
Acute respiratory distress syndrome (ARDS) 
 
Interstitial pneumonia 
      Lung infiltration 
 
Pneumonitis 
      Pulmonary hypertension 
Rare 
Rare 
Rare 
Rare 
Rare 
Rare 
Skin and subcutaneous system disorders 
 
 
Toxic epidermal necrolysis 
Unknown 


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a Incidence is assigned using the following convention:  very common (>1/10); 
common (>1/100 and <1/10); uncommon (>1/1000 and <1/100); rare (>1/10,000 
and <1/1000 ); very rare (<1/10,000, including isolated reports). 
b   Acute diffuse infiltrative pulmonary disease is a MedDRA Lower Level Term 
     which corresponds to a Preferred Term of Interstitial lung disease. 
Source: VELCADE Investigator’s Brochure, Version 12 
 
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 VELCADE 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 Study rationale and selection of drug doses 
In vitro data show that VELCADE has antitumor activity via the following mechanisms: directly 
induces apoptosis of multiple myeloma cells, inhibits activation of NF-κB in multiple myeloma 
cells and in tumor microenvironment, blocks production and intracellular signaling of IL-6. 
Clinical trials of VELCADE in renal transplant subjects without cancer suggest that it has 
activity against non-malignant plasma cells.  Proteasome inhibition by VELCADE induced 
apoptosis of non-malignant human plasma cells and facilitated the treatment of antibody-
mediated humoral rejection of kidney allografts (Perry et al., 2008).  In combination with 
immunosuppressive medications for treating antibody-mediated and cell-mediated acute 
rejection, VELCADE therapy reduced the levels of donor-specific antibodies with minimal 
toxicity in renal transplant recipients (Everly et al., 2008).  Abrogation of anti-HLA 
alloantibodies were successfully achieved with VELCADE therapy in sensitized renal transplant 
recipients (Trivedi et al., 2009). 
In IgA nephropathy, abnormal pIgA1 immunoglobulins are produced by plasma cells in the bone 
marrow and tonsils of subjects (Barratt et al., 2005).  These aberrant pIgA1 antibodies have a 
tendency to form immune complexes in the mesangium and induce an inflammatory response via 
the NF-κB pathway (Ashizawa et al., 2003).  An intra-renal autoimmune response characterized 
by production of cytokines (such as IL-6), growth factors, and adhesion molecules are thought to 
be the cause of progressive renal damage in IgA nephropathy (Lai et al., 2009).  The ubiquitin-
proteasome pathway facilitates the translocation of transcription factor NF-κB from the cytosol 
(where it constitutively resides complexed to its inhibitory protein IκB) into the nucleus.  The 
human kidney proteasome (fully inducible to become iPS) has been purified and characterized 
confirming the observation that the kidney is primed and predisposed to inflammatory response 
in autoimmune glomerular diseases (Baldovino et al., 2006).  Subjects with significant 


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proteinuria not in remission from IgA nephropathy were found to have iPS detected in PBMCs 
(Coppo et al., 2009). Taken together, there is mounting evidence to support the use of 
proteasome inhibitor therapy for aggressive IgA nephropathy. 
 
Investigators in kidney transplant pilot trials provided 4 doses of VELCADE (1 cycle) for 
treating renal transplant rejection (Perry et al., 2008; Everly et al., 2008; Trivedi et al., 2009).  
We propose similar doses (1 cycle on days 1, 4, 8, 11) for induction therapy in subjects with IgA 
nephropathy.  An additional cycle will be given to non-responders following VELCADE 
induction therapy. 


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2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of this study is to investigate ability of VELCADE to induce complete or 
partial remission in subjects with severe IgA nephropathy and risk factors for progression of 
disease.  Complete remission is defined as proteinuria of less than or equal to 300 mg per day.  
Partial remission is defined as reduction in daily proteinuria of greater than 50% from baseline 
(enrollment) proteinuria.  A clinical relapse is defined as a rise in daily proteinuria of greater 
than 50% from nadir following successful induction therapy.  A safety analysis of the use of 
VELCADE in this study population will be performed. 
2.2 Secondary Objectives 
The secondary objectives of this study are to assess clinical outcomes relating to safety and 
efficacy, such as infection, malignancy, preservation of renal function, and reduction in the 
requirement of anti-hypertensive drugs; and to study mechanistic assays to predict remission.  
The proportion of subjects with less than 50% reduction in daily proteinuria or partial responders 
will be assessed. 
 
 
 


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3
INVESTIGATIONAL PLAN
3.1
Overall Design and Plan of the Study
This trial is a single center, open-label, single treatment group assignment, safety and efficacy 
pilot study that will enroll 10 subjects with severe IgA nephropathy.  Participants will receive 4 
doses of VELCADE (1 cycle) to induce clinical remission.  Non-responders after a 4-week 
observation period will receive a second successive cycle of VELCADE. Subjects who do not 
have any response to VELCADE after 2 cycles will be considered treatment failure.  They will 
be taken off the protocol and receive standard renal care by their physicians.  Responders will be 
followed for clinical relapse.  No additional cycles of VELCADE will be provided after a relapse 
per protocol.  Subjects do have the option to receive VELCADE as an off-label therapy after 
discussion with their physicians and be taken off the protocol.  Subjects will be followed for 1 
year after enrollment.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The primary endpoint will be proportion of participants achieving complete or partial remission 
(see section 2.1 for definition of remission).  A safety analysis will be included in the primary 
endpoint.  The secondary endpoints include proportion of subjects with infection, malignancy, 


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deterioration of renal function, and reduction in the requirement of anti-hypertensive drugs.  The 
proportion of subjects with partial response or clinical relapse will also be assessed (see sections 
2.1 and 2.2 for definitions of partial responders and clinical relapse). 
A study flow chart is provided in section 8.1.  Subjects with toxicities will be followed until the 
toxicity resolves or returns to baseline. VELCADE may be administered within ± 1 day of the 
dosing schedule (at least 72 hrs must elapse between VELCADE doses).  For follow-up study 
visits after the administration of VELCADE, a window of ± 5 days will be allowed. 
 
3.2 Selection of Subjects 
The total number of subjects to be enrolled on this study is 10. 
Enrollment is defined as the first day of VELCADE treatment (i.e., Day 1 of cycle 1). 
3.2.1 Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to be enrolled in the study: 
1. Male or female, 18 years of age or older. 
2. Subject is capable of understanding the purposes and risks of the study, is willing to 
participate in and comply with the study, and can give 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. Female subject is either post-menopausal or surgically sterilized or willing to use an 
acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, 
diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the 
study. 
4. Male subject agrees to use an acceptable method for contraception for the duration of the 
study. 
5. Subjects must have biopsy proven severe IgA nephropathy. 
6. Within 14 days before enrollment, creatinine clearance as measured by MDRD formula must 
be greater or equal to 30 cc/min/1.73 m2. 
7. Prior to enrollment, quantified proteinuria (via 24 hr urine collection or spot urine protein 
and creatinine ratio) must be greater or equal to 1000 mg.  
8. Unless contraindicated subject must be on stable doses of ACEI and/or ARB and/or renin 
inhibitor for at least 4 weeks prior to screening. 
 
3.2.2 Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not to be enrolled in the study. 
1. Subject has a platelet count of less than 30× 109/L within 14 days before enrollment. 
2. Subject has an absolute neutrophil count of less than 1.0 × 109/L within 14 days before 
enrollment. 
3. Subject has ≥Grade 2 peripheral neuropathy within 14 days before enrollment. 


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4. Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure (see section 8.3), uncontrolled angina, 
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities. Prior to study entry, any ECG 
abnormality at screening has to be documented by the investigator as not medically relevant. 
5. Subject has hypersensitivity to VELCADE, boron or mannitol. 
6. Female subject is pregnant or breast-feeding.  Confirmation that the subject is not pregnant 
must be established by a negative serum β-human chorionic gonadotropin (β-hCG) 
pregnancy test result obtained during screening.  Pregnancy testing is not required for post-
menopausal or surgically sterilized women. 
7. Subject has received other investigational drugs within 14 days before enrollment. 
8. Serious medical conditions and infections (including HIV, HCV, HBV) or psychiatric illness 
likely to interfere with participation in this clinical study, as determined by review of the 
medical history. 
9. Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception 
of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in 
situ malignancy, or low-risk prostate cancer after curative therapy. 
10. Subject has total bilirubin greater than 1.5 x upper limit of normal. 
 
3.3 Study Treatments 
3.3.1 Clinical Trial Materials 
VELCADE 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.   
3.3.2 Preparation, Handling, and Storage of Drugs 
VELCADE 
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).  To date, stability data indicate that 
the lyophilized drug product is stable for at least 18 months when stored under the recommended 
conditions. Stability studies are ongoing, and Millennium Pharmaceuticals, Inc. will notify the 
investigator should this information be revised during the conduct of the study. 
VELCADE is cytotoxic.  As with all cytotoxic drugs, caution is required when preparing and 
handling VELCADE solutions.  Cytotoxic drugs should only be handled by staff specially 
trained in the safe handling of such preparations. The use of gloves and other appropriate 
protective clothing is recommended.  In case of skin contact, wash the affected area immediately 
and thoroughly with soap and water for at least 15 minutes.  If product contacts eye, immediately 
flush eye thoroughly with water for at least 15 minutes.  Always contact a physician after any 


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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. 
VELCADE Administration and Dosage Schedule 
VELCADE is to be administered (1 cycle) at a dose level of 1.3mg/m2 on days 1, 4, 8, 11 for 
induction.  A second cycle may be repeated for subjects who have not responded within 30 days 
after the induction cycle.  VELCADE may be administered within a window of ± 1 day but must 
be given at least 72 hours after the previous VELCADE dose.  Drug will be administered only to 
eligible subjects under the supervision of the investigator or identified sub-investigator(s).  
Subjects may be treated on an outpatient basis, if possible.  The pharmacist will prepare the drug 
under aseptic conditions.  The amount (in mg) of drug to be administered will be determined 
based on body surface area.  Body surface area is to be calculated based on body weight using a 
standard nomogram (see section 8.2).  The dose should be calculated on Day 1 of each cycle; the 
dose administered should remain the same throughout each cycle but should be recalculated at 
the start of the next cycle.  If a subject experiences a notable change in weight (e.g., loss or gain 
of ≥8 lbs or 3.6 kg) within a cycle, as determined by an unscheduled weight assessment, then the 
subject’s dose should be recalculated at that time. 
The appropriate amount of VELCADE will be drawn from the injection vial and administered as 
an intravenous (IV) push over 3 to 5 seconds followed by a standard saline flush or through a 
running IV line.  Vials are for single use administration. 
   
3.3.3 Dose Modification and Delay 
Dose escalation will not be allowed in any subject, and there must be at least 72 hours between 
each dose of VELCADE.   
 
Before each drug dose, the subject will be evaluated for possible toxicities that may have 
occurred after the previous dose(s).  Toxicities are to be assessed according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE), Version 3.0 (see section 8.5).   
 
All previously established or new toxicities observed at any time, with the exception of 
neuropathic pain and peripheral sensory neuropathy, are to be managed as follows: 


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• If the subject experiences febrile neutropenia, a Grade 4 hematologic toxicity (including a 
platelet count <25 × 109/L) or any ≥Grade 3 non-hematologic toxicity considered by the 
investigator to be related to VELCADE, then drug is to be held. 
 
• For non-hematologic toxicities, VELCADE is to be held for up to 2 weeks until the toxicity 
returns to Grade 1 or better. 
 
• For hematologic toxicities, VELCADE is to be held for up to 2 weeks until the subject has a 
hemoglobin value of 8.0 g/dL, platelet value of 30× 109/L, and absolute neutrophil value of 
1.0 × 109/L.  
 
• Dose interruption or study discontinuation is not required for lymphopenia of any grade.   
 
• If, after VELCADE has been held, the toxicity does not resolve, as defined above, then drug 
must be discontinued. 
 
If the toxicity resolves, as defined above, and VELCADE is to be restarted, the dose must be 
reduced by approximately 25% as follows: 
 
• If the subject was receiving 1.3 mg/m2, reduce the dose to 1.0 mg/m2. 
• If the subject was receiving 1.0 mg/m2, reduce the dose to 0.7 mg/m2. 
• If the subject was receiving 0.7 mg/m2, discontinue drug, unless subject is responding, in 
which case this should be discussed with the PI.  Dose reductions below 0.7 mg/m2 should be 
avoided, but will be considered if subject is having a good response. 
 
Subjects who experience VELCADE-related neuropathic pain and/or peripheral sensory 
neuropathy are to be managed as presented in Table 3.1 Management of Patients with 
VELCADE-Related Neuropathic Pain and/or Peripheral Sensory Neuropathy. 
 


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Table 3-1    
Management of Patients with VELCADE Related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy 
Recommended Dose Modification for VELCADE related Neuropathic Pain and/or Peripheral Sensory or Motor 
Neuropathy  
Severity of Peripheral Neuropathy  
Signs and Symptoms  
Modification of Dose and Regimen  
Grade 1 (paresthesias, weakness and/or loss of reflexes)  
without pain or loss of function  
No action  
Grade 1 with pain or Grade 2 (interfering with  
function but not with activities of daily living)  
Reduce VELCADE to 1.0 mg/m2 
Grade 2 with pain or Grade 3 (interfering with  
activities of daily living)  
Withhold* VELCADE therapy until  
toxicity resolves.  
When toxicity resolves reinitiate with  
a reduced dose of VELCADE at 0.7mg.m2 and change  
treatment schedule to once per week.*  
Grade 4 (Sensory neuropathy which is disabling or motor 
neuropathy that is life threatening or leads to paralysis)  
Discontinue VELCADE 
Grading based on NCI Common Terminology Criteria CTCAE v3.0    
NCI Common Terminology Criteria website - http://ctep.info.nih.gov/reporting/ctc.html  
ADL = activities of daily living 
*Key: 
Reduce by one dose level: 
VELCADE dose reduction from 1.3 to 1.0, or 1.0 to 0.7 mg/m2/dose.  
Reduce by two dose levels: 
VELCADE dose reduction from 1.3 or 1.0 to 0.7 mg/m2/dose. 
Hold:   
 
 
Interrupt VELCADE for up to 2 weeks until the toxicity returns to Grade 1 or better. 
Schedule change:                    Schedule change from VELCADE twice per week (Days 1, 4, 8 and 11 on a Q3W cycle)       
to once per week (Days 1, 8, 15, and 22 on a Q5W cycle).  If the treatment schedule is already once weekly, then it 
should remain once weekly. 
The neurotoxicity-directed questionnaire (see section 8.6) is a useful tool for determining the 
presence and intensity of neuropathic pain and/or peripheral neuropathy from the subject’s 
perspective.  Neuropathic symptoms are more prominent than abnormalities on the clinical 
examination.  After the subject completes the neurotoxicity-directed questionnaire, the 
questionnaire should be reviewed to assist with the evaluation of the onset and intensity of 
peripheral neuropathy and other neurotoxicities that may possibly require intervention or dose 
modification. 
 
Dosage in Subjects with Hepatic Impairment  
 
Subjects with mild hepatic impairment do not require a starting dose adjustment and should be 
treated per the recommended VELCADE dose. Subjects with moderate or severe hepatic impairment 
should be started on VELCADE at a reduced dose of 0.7 mg/m
2 
per injection during the first cycle, 
and a subsequent dose escalation to 1.0 mg/m
2 
or further dose reduction to 0.5 mg/m
2 
may be 
considered based on subject tolerance (see Table 3).  
 
 
 


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Table 3: Recommended Starting Dose Modification for VELCADE in Patients with Hepatic 
Impairment  
Bilirubin 
Level  
SGOT (AST) Levels  
Modification of Starting Dose  
≤ 1.0x ULN  
> ULN  
None  
Mild  
> 1.0x−1.5x ULN  
Any  
None  
Moderate  
> 1.5x−3x ULN  
Any  
Severe  
> 3x ULN  
Any  
Reduce VELCADE to 0.7 mg/m
2 
in the first cycle. 
Consider dose escalation to 1.0 mg/m
2 
or further 
dose reduction to 0.5 mg/m
2 
in subsequent cycles 
based on patient tolerability.  
 
3.3.4        Treatment Assignment 
This trial is a single center and open-label with single treatment group assignment. 
3.3.5      Blinding, Packaging, and Labeling 
VELCADE will be supplied in vials as open-label stock.  Both the box label and vial label will 
fulfill all requirements specified by governing regulations.   
3.3.6         Concomitant Treatment 
 
Prophylaxis 
Subjects will be given oral acyclovir within the first month after enrollment for a total of six  
months as a prophylactic agent to prevent reactivation of varicella zoster virus (shingles).  Oral 
acyclovir will be dosed at 400mg daily (Pour et al., 2009). 
 
Titration of Concurrent Therapy 
The following medications should not be titrated up (or increased) during the duration of the 
study: 
• ACEI 
• ARB 
• Renin inhibitor 


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Prohibited Concurrent Therapy 
• Any investigational agent other than VELCADE. 
3.3.7 
Treatment Compliance 
All drugs will be administered to eligible subjects 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, subjects’ 
height, body weight, and body surface area (see section 8.2), 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 Subject Participation 
Subjects will be screened for eligibility to participate in the study.  Treatment consists of up to 2 
cycles of VELCADE infusion if required (see section 3.1).  A single cycle of treatment is 
comprised of four doses of VELCADE infusion over a 2-week period.  Subjects will be followed 
for 1 year after enrollment if they qualify to participate in the trial.  Enrollment is defined as the 
first day of VELCADE treatment (i.e., Day 1 of cycle 1). 
 
3.5 Termination of Treatment and/or Study Participation 
Subjects 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 
subjects 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 
• Subject request 
• Protocol violations 
• Non-compliance 
• Administrative reasons 
• Failure to return for follow-up 
• General or specific changes in the subject’s condition unacceptable for further treatment 
in the judgment of the investigator 


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• Progressive disease at any time (including worsening of serum creatinine) 
At the time of withdrawal, all study procedures outlined for the End of Study visit (Month 12) 
should be completed.  The primary reason for a subject’s withdrawal from the study is to be 
recorded in the source documents. 
Participants who are non-responders prior to or following the second successive cycle of 
VELCADE may choose to return to their physicians for further care and be taken off the 
protocol. 
3.6 Efficacy, Pharmacodynamic/Pharmacogenomic/Correlative studies, and Safety 
Measurements 
3.6.1 Efficacy Measurements 
Quantification of urinary protein will be made after treatment to assess primary and secondary 
endpoints.  Other variables to be assessed for secondary endpoints include blood pressure, 
hematuria (urinalysis), and serum creatinine. 
 
 
 
3.6.2 Safety Measurements 
The following variables will be monitored after enrollment: 
1) Complete blood count 
2) Liver function test 
3) Serum immunoglobulin profile 
4) Renal function (24 hr urine creatinine clearance) 
5) Serum uric acid 
6) Clinical signs of infections 


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4 ADVERSE EVENTS 
4.1 Definitions 
4.1.1 Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a subject 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 (e.g., 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 subject 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 subject was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., 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 subject/event outcome or action criteria described above and are 
usually associated with events that pose a threat to a subject’s life or functioning.  A severe 


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adverse event does not necessarily need to be considered serious.  For example, persistent nausea 
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 serious adverse event (SAE) regardless of relationship with 
any study drug or expectedness to Millennium 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.  
Investigator-sponsor must also provide Millennium 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’s Product Safety Department 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.  
 
SAE Reporting Contact Information: North America 
PPD, Inc. 
Safety and Medical Management, US 
Fax: +1 888-488-9697 
Hotline number (available 24/7): 1-800-201-8725  
 
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 subject’s study 
participation will be recorded in the source documents.  All SAEs should be monitored until they 


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are resolved or are clearly determined to be due to a subject’s stable or chronic condition or 
intercurrent illness(es). 
 
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.  
Millennium must also be contacted immediately by faxing a completed Pregnancy Form to either 
Millennium Product Safety for North America or PRA Safety Management Services for rest of 
world.  The pregnancy must be followed through outcome (i.e. delivery, still birth, miscarriage). 
 


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5 STATISTICAL PROCEDURES 
5.1 Sample Size Estimation 
This is a pilot study consisting of 10 subjects.  The analyses will be descriptive.  However, to the 
extent possible, estimates obtained in the study will be interpreted in the context of data from 
historical cohorts. 
5.2 Randomization and Stratification 
This is an open label and single treatment arm study. 
5.3 Populations for Analysis 
Adult subjects with IgA nephropathy will be enrolled.  
5.4 Procedures for Handling Missing, Unused, and Spurious Data 
Subjects whose outcome is unknown will be considered as efficacy failures.  There will be no 
other imputation of missing data. 
5.5 Statistical Methods 
5.5.1 Baseline Comparisons 
Summary descriptive statistics for baseline and demographic characteristics will be collected for 
all enrolled participants.  Demographic data will include age, race, sex, body weight, height, 
baseline proteinuria, creatinine clearance, and serum creatinine; these data will be presented in 
the following manner: 
1) Continuous data (i.e., age, body weight, and height etc.) will be summarized descriptively 
by mean, standard deviation, and range. 
2) Categorical data (i.e., sex and race) will be presented as enumerations and percentages. 
5.5.2 Efficacy Analysis 
The following analysis samples will be utilized for statistical analyses: 
1) Intent-to-treat (ITT) sample: Any subjects who received a dose of the study drug. 
2) Per-protocol (PP) sample: All enrolled subjects who received at least 1 cycle of the study 
drug and have primary efficacy assessment data. 
The proportion of participants who have achieved complete or partial remission or who are 
partial responders will be analyzed using PP sample and descriptively summarized with a two-
sided, 95% CI.  Proportion of participants who have improved renal function, less hematuria, and 


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less anti-hypertensive drug requirements will be analyzed using ITT sample. 
5.5.3 Safety Analysis 
All subjects who received any study drug will be included in the safety sample.  Participants in 
the safety sample will be included in all safety analyses.  All adverse events, including 
infections, malignancies, morbidity, and various side-effects from the study drug will be reported 
using CTCAE version 3.0. 
5.5.4 Correlative studies 
PAXgeneTm and serum separator tubes will be used to collect blood samples from participants 
prior to and after VELCADE therapy.  Urine samples will also be collected from participants.  
mRNA of relevant genes will be analyzed from blood and urine to be used as predictors of 
response to therapy.  Additional correlate assessments may also be performed in the future. 
5.6 Data Monitoring 
Analysis of primary and secondary endpoints will be performed after 5 subjects have been 
enrolled. 
5.7 Procedures for Reporting Deviations to Original Statistical Analysis Plan 
The principal features of the study design and of the plan for statistical analysis of data are 
outlined in this protocol and in the subsequent statistical analysis plan.  Any changes in these 
principal features will be subject to review by the study sponsor.  These changes will be 
described in the final report as appropriate. 


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6 ADMINISTRATIVE REQUIREMENTS 
6.1 Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP), FDA regulations and other 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 8.4) and Institutional Review Board (IRB) requirements.  The IRB will 
review all appropriate study documentation in order to safeguard the rights, safety and well being 
of the subjects.  The study will only be conducted at sites where IRB approval has been obtained.  
The protocol, Investigator’s Brochure, informed consent, advertisements (if applicable), written 
information given to the subjects (if applicable), safety updates, annual progress reports, and any 
revisions to these documents will be provided to the IRB by the investigator.  Millennium 
requests that informed consent documents be reviewed by Millennium or designee prior to IRB 
submission.   
6.3 Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject prior to study participation.  The method of obtaining and documenting the informed 
consent and the contents of the consent will comply with ICH-GCP, IRB, and all applicable 
regulatory requirement(s). 
 
A separate Authorization Form for subject authorization to use and disclose personal health 
information under the U.S. Department of Health and Human Services Standards for Privacy of 
Individually Identifiable Health information (HIPAA), 45 CFR Parts 160 and 164 regulations 
will also be obtained, as per IRB policy. 
6.4 Subject Confidentiality 
In order to maintain subject privacy, all data capture records, drug accountability records, study 
reports and communications will identify the subject by initials and the assigned subject number.   
 
Subject medical information obtained as part of this study is confidential, and must not be 
disclosed to third parties, except as noted below. The subject may request in writing that medical 
information is given to his/her personal physician. 
 
The investigator/institution will permit Millennium monitor(s) and auditor(s) or its designees, the 
FDA and/or other applicable regulatory authority(ies) access to the subject’s original medical 
records for verification of data gathered on the data capture records and to audit the data 


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collection process. The access may consist of study-related monitoring, audits, IRB reviews, and 
FDA inspections.  Release of research results should preserve the privacy of medical information 
and must be carried out in accordance with HIPAA regulations.  The subject’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 by the 
IRB and the appropriate regulatory authority(ies).  Changes to the protocol will require approval 
from Millennium and written IRB approval prior to implementation, except when the 
modification is needed to eliminate an immediate hazard(s) to subjects.  The IRB may provide, if 
applicable regulatory authority(ies) permit, expedited review and approval for minor change(s) in 
ongoing studies that have the approval of the IRB.  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 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 subject, 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 subject 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 subjects 
• Failure to enter subjects at an acceptable rate 


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• 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).   
 


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Richardson PG, Barlogie B, Berenson J et al. A Phase II study of VELCADE in Relapsed, 
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Richardson PG, et al., VELCADE or High-Dose Dexamethasone for Relapsed Multiple 
Myeloma. N Engl J Med 2005; 352:2487-98.  
Richardson et al, VELCADE 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. 
Samuels JA, Stripploli GFM, Craig JC, Schena FP, Molony DA. Immunosuppressive treatments 
for immunoglobulin A nephropathy: a meta-analysis of randomized controlled trials. Nephrology 
2004;9:177-185. 
Steiner P, Neumeier H, Lightcap E, Sadis S, Pien C, Pink M et al. Adaptation of Human Tumor 
Cell Lines to PS-341. AACR-NCI-EORTC International Conference, 2001; Miami Beach, FL. 
Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, MA 02139. Abstract  
Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-341 in 
cancer therapy. Clin Cancer Res 1999; 5 (9):2638-45. 
Trivedi HL, Terasaki PI, Feroz A, Everly MJ, Vanikar AV, Shankar V et al. Abrogation of anti-
HLA antibodies via proteasome inhibition. Transplantation 2009;87:1555-1561. 
 
VELCADE (bortezomib) [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; 
2003. 
Wada J, Sugiyama H, Makino H. Pathogenesis of IgA nephropathy. Semin Nephrol 2003; 
23:556-563. 
 
 
 


VELCADE® Therapy for Severe IgA Nephropathy Protocol # X05320 
 
FINAL 
The Rogosin Institute 
 
v. 1.6 
VELCADE® IIS Protocol X05320 
 
CONFIDENTIAL 
 
Page 42 
8 APPENDICES 
 


VELCADE Therapy for Severe IgA Nephropathy 
Protocol # X05320 
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The Rogosin Institute 
v. 1.6 
VELCADE® IIS Protocol X05320 
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8.1 Study Flow Chart 
VELCADE for severe IgA nephropathy1,2,3 
 
 
 
1st Cycle 
 
 
 
2nd Cycle (if 
needed) 
 
 
 
 
 
 
 
 
 
 
 
Service/Procedure/Activity 
Screen 
Day 1 
Day 4 
Day 8 
Day 11 
Day 18 
Day 25 
Day 39 
Day 43 
Day 46 
Day 50 
Day 53 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
Month 8 
Month 9 
Month 10 
Month 11 
Month 12 
Physical Exam 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry-10 
X 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Liver Panel 
X 
X 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Urine Protein/Creatinine 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
X 
X 
 
X 
X 
 
 
X 
 
 
X 
Serum Ig Profile 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
CBC 
X 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
 
X 
Serum Uric Acid 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
MDRD Calculation GFR 
X 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
24 Hr Creatinine Clearance 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Intervention: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VELCADE 1.3 mg/m2 (1st 
cycle) 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If needed 2nd cycle of 
VELCADE 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pax Gene Blood Collection 
X 
 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Serum Tube  
X 
 
 
X 
 
X 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Plasma Tube 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Urine Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1. Clinical Trial to be conducted at Weill Cornell CTSC except for outpatient visits at The Rogosin Institute on Month(s) 4, 5, 7, 8, 10 and 11. 
2. Non-responders will be offered “standard therapy” at the discretion of their physicians.  
3.  Patients with toxicities to VELCADE will be followed until the toxicity resolves or returns to baseline.  
 
 


VELCADE Therapy for Severe IgA Nephropathy 
Protocol # X05320 
FINAL 
The Rogosin Institute 
v. 1.6 
VELCADE® IIS Protocol X05320 
CONFIDENTIAL 
page 44 
8.2 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): 
BSA = 
3131
)
(
)
(
lbs
Wt
inches
Ht
×
 
or 
BSA = 
3600
)
(
)
(
kg
Wt
cm
Ht
×
 
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 subjects, the Cockroft-Gault formula will tend to overestimate the 
creatinine clearance. (Adipose tissue tends to contribute little creatinine requiring renal 
clearance.) 


VELCADE Therapy for Severe IgA Nephropathy 
Protocol # X05320 
FINAL 
The Rogosin Institute 
v. 1.6 
VELCADE® IIS Protocol X05320 
CONFIDENTIAL 
page 45 
8.3 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 Therapy for Severe IgA Nephropathy 
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8.4   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 


VELCADE Therapy for Severe IgA Nephropathy 
Protocol # X05320 
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The Rogosin Institute 
v. 1.6 
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consent for themselves, for those who may be subject to giving consent under duress, for 
those who will not benefit personally from the research and for those for whom the research 
is combined with care. 
9. Research Investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration. 
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. 


VELCADE Therapy for Severe IgA Nephropathy 
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8. Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed.  Physicians should cease any investigation if the risks are found to 
outweigh the potential benefits or if there is conclusive proof of positive and beneficial 
results. 
9. Medical research involving human subjects should only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the subject.  This is especially 
important when the human subjects are healthy volunteers. 
10. Medical research is only justified if there is a reasonable likelihood that the populations in 
which the research is carried out stand to benefit from the results of the research. 
11. The subjects must be volunteers and informed participants in the research project. 
12. The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality 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 


VELCADE Therapy for Severe IgA Nephropathy 
Protocol # X05320 
FINAL 
The Rogosin Institute 
v. 1.6 
VELCADE® IIS Protocol X05320 
CONFIDENTIAL 
page 49 
advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population.  The 
specific reasons for involving research subjects with a condition that renders them unable to 
give informed consent should be stated in the experimental protocol for consideration and 
approval of the review committee.  The protocol should state that consent to remain in the 
research should be obtained as soon as possible from the individual or a legally authorized 
surrogate. 
18. Both authors and publishers have ethical obligations.  In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results.  Negative as 
well as positive results should be published or otherwise publicly available.  Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared in 
the publication.  Reports of experimentation not in accordance with the principles laid down 
in this Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
1. The physician may combine medical research with medical care, only to the extent that the 
research is justified by its potential prophylactic, diagnostic or therapeutic value.  When 
medical research is combined with medical care, additional standards apply to protect the 
patients who are research subjects. 
2. The benefits, risks, burdens and effectiveness of a new method should be tested against 
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 judgment 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 Therapy for Severe IgA Nephropathy 
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The Rogosin Institute 
v. 1.6 
VELCADE® IIS Protocol X05320 
CONFIDENTIAL 
page 50 
 
8.5 Common Terminology Criteria for Adverse Events Version 3.0 
http://ctep.cancer.gov/reporting/ctc.html 
 
8.6 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.