Clinical trial NCT02370693
Conditions: Lung Diseases, Interstitial Systemic Sclerosis Scleroderma
Keywords: mycophenolate lung scarring
Sponsor: Northwestern University
Start date: 2016-03-01; Completion date: 2020-01-01
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to look at whether bortezomib, mycophenolate or the combination of both is better to treat scarring of the lung caused by Systemic Sclerosis.

Detailed description:
Systemic sclerosis (SSc) is a chronic multisystem autoimmune connective tissue disease for which the etiology remains unknown. The prevalence for SSc is between 19-75 cases per 100,000 and it is more frequent in women, with a peak occurrence in the 4th or 5th decade of life. Morbidity and Mortality in SSc are substantial and pulmonary complications are now the leading cause of death among patients with SSc.

Bortezomib is an FDA approved therapy for the treatment of multiple myeloma and other malignancies. The investigators have data that bortezomib inhibits transforming growth factor (TGF) - signaling in vitro and promotes normal repair and prevents against lung fibrosis in the TGF-mediated intratracheal bleomycin mouse model as well as in a mouse model for skin fibrosis. This is consistent with other data in the literature that proteasomal inhibition can prevent the development of fibrosis. Further there are multiple reports on the efficacy of bortezomib in ameliorating chronic graft-versus-host disease in patients after allogeneic hematopoietic stem cell transplant for multiple myeloma. Bortezomib was also well tolerated in the large clinical trials of multiple myeloma patients with neuropathy and thrombocytopenia the primary adverse events. No pulmonary toxicities were reported in these studies.

Mycophenolate mofetil (CellCept or Myfortic) belongs to a class of medications known as immunosuppressives. This medication was used originally in the management of patients with organ transplants, but is now recommended in the treatment of some autoimmune diseases such as SSc.

Mycophenolate mofetil targets an enzyme in the body called inosine monophosphate dehydrogenase that is important for the formation of deoxyribonucleic acid (DNA) in cells. By interfering with DNA, the medication impairs function of immune system cells that become overactive in autoimmune diseases. Mycophenolate mofetil is currently approved in the treatment of patients with SSc.

This study is being conducted to establish the safety and tolerability of bortezomib in SSc patients at high risk for pulmonary disease progression. In addition, the study will examine the effect of bortezomib on the rate of forced vital capacity (FVC) decline (a physiologic parameter closely associated with disease outcome) and other clinical parameters. In addition the investigators will also measure the effect of bortezomib on biomarkers associated with fibroblast activation. If successful, the study will provide the rationale for a multi-center placebo controlled trial to test the efficacy of bortezomib in SSc patients at high risk for progressive pulmonary disease.

Arms: arm 1: Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks arm 2: Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month and mycophenolate mofetil 1.5 g orally twice daily for 24 weeks
Interventions: intervention 1: Bortezomib intervention 2: Placebo intervention 3: Mycophenolate mofetil
Intervention descriptions: intervention 1: Bortezomib 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks intervention 2: Placebo (normal saline) 1.3 mg/m² subcutaneously (or IV push if unable to tolerate subcutaneous injection) once per week for the first two weeks per month for 24 weeks intervention 3: Mycophenolate mofetil 1.5 g twice a day orally for 24 weeks

Protocol documents:
Prot_SAP_000.pdf: 
1
Clinical Trial Protocol
Title: Comparing and Combining Bortezomib and Mycophenolate in SSc Pulmonary Fibrosis
Funding Sponsor: NIH
Grant Number: R34HL122558
PROTOCOL VERSION
DATE OF PROTOCOL
# 9
10/1/2019
Investigator and Study Center
Manu Jain MD, MS* 
Feinberg School of Medicine 
Northwestern University
*240 E. Huron Avenue M332
Chicago, Illinois
60611
Telephone: 312-503-4242 
m-jain@northwestern.edu
IRB #: STU00101010 Approved by NU IRB for use on or after 8/14/2020 through 8/13/2021.
ClinicalTrials.gov ID: NCT02370693


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SUMMARY OF PROPOSED WORK
Background: Systemic sclerosis (SSc) is a chronic multisystem autoimmune connective 
tissue disease for which the etiology remains unknown. The prevalence for SSc is between 19- 
75 cases per 100,000 and it is more frequent in women, with a peak occurrence in the 4th or 5th 
decade of life. Morbidity and Mortality in SSc are substantial and pulmonary complications are 
now the leading cause of death among patients with SSc. The most profound SSc pulmonary 
manifestations are pulmonary arterial hypertension (PAH) and pulmonary fibrosis (PF). Skin 
fibrosis is also a significant cause of morbidity. Pulmonary and skin fibrosis is marked by 
fibroblast activation, increased extracellular matrix synthesis and progressive replacement of 
normal tissue architecture. While the role of resident fibroblasts in development of pulmonary 
fibrosis is not questioned, the specific cells, signals and mechanisms that trigger and sustain 
their activation are subjects of extensive investigation. Transforming growth factor-beta (TGF-
) has been implicated as a central mediator in the pathogenesis of both pulmonary and skin 
fibrosis as well as pulmonary hypertension.
SSc is an orphan disease and as such resources devoted towards investigating 
pathophysiological mechanisms and developing novel therapies for SSc associated fibrosis are 
limited. Treatment approaches for SSc associated fibrosis or tissue fibrosis in general 
represents a significant unmet need in medicine. Despite the absence of proven for SSc 
associated pulmonary fibrosis, Mycophenolate Mofetil has become 1st line therapy at many 
SSc Centers.
The SSc program at Northwestern is one of the leading programs in the country. There are 
robust clinical and research efforts devoted to providing state of the art patient care as well as 
exploring the pathophysiology of tissue fibrosis and identifying novel therapeutic targets. The 
program has exceptional resources to identify new potential therapies and translate them 
efficiently to the clinic. As part of our effort, we began experiments exploring the role of 
proteasomal inhibition in tissue fibrosis. Our interests coalesced around our expertise in the 
ubiquitin proteasomal protein degradation pathway and intriguing hints in the literature that 
proteasomal inhibition may protect against tissue fibrosis in some animal models. We decided 
to use bortezomib a small molecule proteasome inhibitor in our experiment since it was FDA 
approved and there was extensive human safety experience already. In our initial experiments, 
bortezomib was administered to mice beginning seven to fourteen days after the intratracheal 
(pulmonary fibrosis model) or intradermal administration of bleomycin (skin fibrosis model) and 
lung and skin fibrosis were measured after 21 (and 28) or 40 days, respectively. We also found 
similar efficacy for bortezomib in the asbestos model of lung fibrosis. Further, to examine the 
mechanism of this protection, bortezomib was administered to primary normal lung fibroblasts 
and primary lung and skin fibroblasts obtained from patients with idiopathic pulmonary fibrosis 
and scleroderma, respectively. Our results showed that bortezomib promoted normal repair 
and showed dramatic reduction in lung and skin fibrosis when administered beginning 7-14 
days after the initiation of bleomycin. In primary human lung fibroblasts from normal individuals 
and patients with idiopathic pulmonary fibrosis and in skin fibroblasts from patients with 
scleroderma, bortezomib inhibited TGF-β mediated transcription by inhibiting transcription 
induced by activated Smads.  This inhibition required an increase in the abundance and activity
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of the nuclear hormone receptor Peroxisome proliferator-activated receptor-gamma (PPAR-) a 
repressor of Smad-mediated transcription. Based on these results we have developed the 
following hypothesis.
Hypothesis: Proteasomal Inhibition will result in TGF- antagonism and a potent anti-fibrotic 
effect. Thus we hypothesize that bortezomib will lead to stabilized FVC in patients with SSc at 
high risk for disease progression.
Proposal: A randomized pilot trial in which bortezomib or placebo is added to MMF for 24 
weeks in SSc-ILD patients. Toxicity and tolerability data are the primary endpoints. The primary 
clinical endpoint is the annualized change forced vital capacity (FVC) and there are multiple 
secondary endpoints.
In summary our published results are tremendously exciting since they identify an FDA 
approved drug that may show efficacy in pulmonary and skin fibrosis, diseases for which there 
are no effective treatments. Our proposed trial will provide the rationale for a pivotal, multi- 
center trial of proteasomal inhibition in SSc.
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PROTOCOL SUMMARY
TITLE: PROTEASOMAL INHIBITION IN SYSTEM SCLEROSIS (PRISS)
Objectives
THE PRIMARY OBJECTIVE OF THIS STUDY IS TO:

To assess the safety and tolerability of bortezomib with MMF in System Sclerosis (SSc) 
patients at high risk of progression of pulmonary disease

To assess the effect of bortezomib with MMF on lung function in SSc patients at high 
risk of progression of pulmonary disease
THE SECONDARY OBJECTIVES OF THIS STUDY ARE TO:

To  assess  the  effect  of  bortezomib  with  MMF  on  Quality  of  Life  and  respiratory 
symptoms in SSc patients at high risk of progression of pulmonary disease

To assess the effect of bortezomib with MMF skin fibrosis in System Sclerosis (SSc) 
patients at high risk of progression of pulmonary disease
Exploratory objective

To assess the effect of bortezomib with MMF on serum biomarkers

To assess the effect of bortezomib with MMF on aberrant gene expression in skin 
biopsies from SSc patients at high risk for disease progression
STUDY DESIGN
Study Overview
This is a pilot randomized clinical trial of adding bortezomib or placebo to MMF in SSc System 
Sclerosis (SSc) patients at high risk of progression of pulmonary disease
Primary Efficacy Endpoint

Annualized change in forced vital capacity (FVC)
Primary Safety Endpoint

Incidence of Serious Adverse Events (SAEs)
Secondary Endpoints

Change in Modified Rodnan Skin Score

Change in SF-36

Change in St. George’s Respiratory Dyspnea Score

Change in Hopkins Skin Score (Exploratory)

Change in Promis-29 (Exploratory)

Change in FACIT-dyspnea Score (Exploratory)
Exploratory Endpoints

Change in Serum Biomarkers

Change in Gene Expression Profile (Skin Biopsies and monocyte/macrophages)
PATIENT POPULATION

Patients with SSc who have active pulmonary disease (as defined below)
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NUMBER OF PATIENTS

30
Enrollment: An expert panel has recently recommended that efforts be made to enrich SSc 
cohorts at greater risk for disease progression(1). With this in mind and in order to maximize 
the risk-benefit ratio of a novel therapy in SSc patients we have identified risk factors 
associated with pulmonary disease progression. The rationale is provided below.
Rationale: In the NIH-funded SLS-1 study of SSc patients, the forced vital capacity (FVC) was 
4.16% higher in the cyclophosphamide (CYC) treated group compared to the placebo treated 
group after 12 months. This improvement dissipated after 24 months. The overall magnitude of 
the non-durable response to CYC was modest, which combined with the potential toxicity of 
CYC has led to limited enthusiasm for treating SSc patients with CYC. Another observation 
from the SLS-1 study was the considerable heterogeneity in clinical course in the placebo and 
CYC treated cohorts. Investigation of factors that were associated with accelerated loss of FVC 
in the placebo treated patients and significant treatment response in those randomized to CYC 
identified extent of pulmonary and skin fibrosis as assessed by HRCT (Fibmax) and the Modified 
Rodnan Skin Score (MRSS) (2). Further these factors were most useful in those diagnosed 
with SSc within 2-3 years of trial entry(3). These data are similar to a large observational cohort 
in which disease extent on chest HRCT or an FVC < 70% predicted was associated with a 
higher mortality(4). Another subset of patients who is at increased risk of mortality is that with 
rapid loss of lung function, regardless of disease duration (5). Based on these considerations 
we propose inclusion criteria designed to enrich SSc subjects at high risk for disease 
progression and most likely to benefit from treatment.
INCLUSION CRITERIA
1.
Meet established criteria for diffuse or limited SSc and evidence of pulmonary at high 
risk of progression with or without progressive skin disease.
a.
Definition includes subjects who meet the ACR criteria for scleroderma
b. High Risk of disease progression (see rationale) will be defined as follows
i.
If first non-Raynaud’s manifestation of SSc < 36 months, then if any of 
the following are true:
1.
FVC <70% predicted 
or
2.
HRCT Fibmax >3
or
3.
FVC < 85% and MRSS increase > 5 over 6 months
ii.
Regardless of disease duration
1.
Fall in FVC > 10% over the preceding 12 months or less in the 
absence of prior therapy or another identified causative process 
as assessed by the primary scleroderma physician
2.
Fall in FVC > 10% over 12 months on at least 12 months of 
prior therapy
2.
Age > 18 years
3.
Ability to give informed consent.
4.
Willingness to discontinue present therapy for the duration of the study
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5.
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.
6.
Male subject agrees to use an acceptable method for contraception for the duration of 
the study.
7.
No evidence of acute infection 
8.  ANC >1000
9.
Platelets >75,000
10. Stable MMF dose for 8 weeks
Exclusion Criteria
1.
Inability to give informed consent or comply with protocol procedures
2.
FVC < 40% or DLCO <30% predicted
3.
Patient has a platelet count of less than 50,000 within 14 days before enrollment.
4.
Patient has an absolute neutrophil count of less 1000 within 14 days before enrollment.
5.
Patient has a calculated or measured creatinine clearance of < 20 ml/minute within 
14 days before enrollment.
6.
Patient   has   Grade 2   peripheral   neuropathy   by   history   within   14 days   before 
enrollment.
7.
Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled angina, 
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities. Prior to study entry, any ECG 
abnormality at Screening has to be documented by the investigator as not medically 
relevant.
8.
Patient has hypersensitivity to bortezomib, boron or mannitol.
9.
Female subject is pregnant or breast-feeding. Confirmation that the subject is not 
pregnant must be established by a negative serum -human chorionic gonadotropin (- 
hCG) pregnancy test result obtained during screening. Pregnancy testing is not 
required for post-menopausal or surgically sterilized women.
10.Patient has received other investigational drugs within 4 weeks before enrollment
11.Serious   medical   co-morbidity   which   in   the  opinion  of  the  investigator  makes 
participation in the study too high risk
12.Psychiatric illness likely to interfere with participation in this clinical study.
STUDY DESIGN AND METHODOLOGY

This is a pilot study in which patients who meet entry criteria will be randomized 
to receive bortezomib or placebo as add on treatment for MMF for 24 weeks. 
Fifteen patients will be randomized to receive bortezomib or placebo.
TREATMENTS ADMINISTERED
Rationale: The standard dose of bortezomib in multiple myeloma is 1.3 mg/m2. This is also the 
dose of bortezomib which has been well tolerated in an ongoing study of GVHD patients. Thus
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we will use this dose of bortezomib in our study. The MMF dose is the standard dose used in 
clinical practice for SSPF.

Bortezomib  1.3 mg/m2   once a week
x 2 by Subcutaneous  injection  or IV 
infusion (every 4 weeks Monthly) or placebo x 3 4-week cycles (12 weeks) and 
then Bortezomib 1.3 mg/m2   once a week by Subcutaneous  injection  or IV 
infusion (every 4 weeks Monthly) or placebo x 3 4-week cycles (12 weeks)

MMF 1.5 g twice a day orally for 24weeks.
STATISTICAL PROCEDURES
Based on a previous study (2), we will assume that the high risk subgroup of SSc-ILD patients 
in this study will have had an annualized fall in FVC of 5% if not treated. We will assume that 
bortezomib/MMF group will work at least as well as CYC in SLS1 and better than placebo/MMF 
which will lead to a non-worsening and perhaps improvement in FVC. We will define non- 
worsening as a flat (0%) slope in FVC. The reported standard deviation of the difference from 
baseline was 5%. These data in addition to SLS2 results will facilitate future phase 3 trial 
design and corresponding power calculations, by providing estimates of variability and 
plausible effect size after each treatment. Additional analyses will involve linear random effects 
model to fit observations over time for each subject, as well as for all (random) subjects 
together to compare the two treatment groups. This will provide information about components 
of variance present in this type of data, under such or similar circumstances, to be used in 
future study planning. Thus we will be able to use the proposed study to estimate the range of 
within subject variability as well as between subjects variability inherent in a general mixed 
model. We will use command xtmixed in Stata statistical software (www.stata.com).
ANALYSIS PLAN
Patients who receive at least 1 dose of bortezomib/ placebo will be termed the intention to treat 
(ITT) population. Patients who complete at least 2/3 of the bortezomib/placebo doses in the trial 
will be termed per protocol population (PP) and analyzed separately. The main analysis will be 
performed on the ITT group where measurements will be taken at the enrollment and the 
primary endpoint visit. In an alternative statistical analysis we will incorporate as a covariate the 
actual length of time between ‘first’ and ‘last’ measurements as it may vary from patient to 
patient if there is dropout prior to completing treatment. The primary and secondary endpoints 
will be analyzed using the ITT and PP populations. Results from the ITT analysis will take 
precedence over findings from the PP analysis. In addition, where possible, pattern mixture 
models will be used to assess the level of ‘randomness’ for missing data.
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Contents
1.  BACKGROUND AND STUDY RATIONALE
1.1. Overview of Disease………………………………………………………………….11 
1.2. Bortezomib…………………………………………………………………………….12
1.3. Study rationale and selection of drug doses……………………………………….24 
1.4.      MMF…………………………………………………………………………………….24
2.  Study Objectives……………………………………………………………………………24
2.1. Primary Objective……………………………………………………………………..24
2.2. Secondary Objectives………………………………………………………………..24
2.3. Exploratory Objectives………………………………………………………………..24
3.  Investigational Plan………………………………………………………………………..25
3.1. Overall Design and Plan of Study……………………………………………………25 
3.2. Selection of Patients…………………………………………………………………..25 
3.2.1.  Inclusion Criteria………………………………………………………………..25 
3.2.2.  Exclusion Criteria……………………………………………………………….26 
3.3. Study Treatments………………………………………………………………………27
3.3.1.  Clinical Trial Materials………………………………………………………….27
3.3.2. Preparation, Handling and Storage of Drugs………………………………..27
3.3.3. Dose Modification and Delay………………………………………………….28 
3.3.4. Treatment Assignment ………………………………………………………..31
3.3.5. Blinding, Packaging and Labeling…………………………………………….31 
3.3.6. Concomitant Treatment………………………………………………………..31 
3.3.7.  Treatment Compliance…………………………………………………………32
3.3.8.  Concurrent Medications………………………………………………………..32
3.4. Duration of Treatment, Patient Participation and Study Procedures……………..32
3.4.1. Summary of Study Visits……………………………………………………….32 
3.4.2.  Study Procedures……………………………………………………………….34
3.5. Termination of Treatment and/or Study Participation………………………………37
3.6. Efficacy, Pharmacodynamic/Correlative Studies and Safety Measurements……37
3.6.1.  Efficacy Measurements…………………………………………………………37
3.6.2. Pharmacodynamic Measurements…………………………………………….37 
3.6.3.  Safety Measurements…………………………………………………………..37
4.  Adverse Events………………………………………………………………………………37
4.1. Definitions………………………………………………………………………………..38
4.1.1. Adverse Event (AE) Definition…………………………………………………38
4.1.2. Serious Adverse Event (SAE) Definition……………………………………...38
4.2. Procedures of AE and SAE Reporting………………………………………………..39
4.3. Monitoring of Adverse Event and Period of Observation…………………………...39 
5.  Statistical Procedures………………………………………………………………………..39 
5.1. Sample Size Estimation………………………………………………………………...39 
5.2. Populations for Analysis………………………………………………………………...39
5.3. Procedures for Handling Missing, Unused and Spurious Data……………………..40
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5.4. Statistical Methods……………………………………………………………………….40
5.4.1.  Baseline Variables………………………………………………………………..40
5.4.2.  Efficacy Analysis………………………………………………………………….40
5.4.3.  Safety Analysis and stopping rules……………………………………………..41
5.5. Procedures for Reporting Deviations to Original Statistical Analysis Plan………...41 
6.  Administrative Requirements………………………………………………………………...41
6.1. Good Clinical Practice…………………………………………………………………..41 
6.2. Ethical Considerations…………………………………………………………………..41
6.3. Patient Information and Informed Consent……………………………………………41 
6.4. Patient Confidentiality……………………………………………………………………42 
6.5. Protocol Compliance…………………………………………………………………….42 
6.6. On-site Audits…………………………………………………………………………….42 
6.7. Drug Accountability………………………………………………………………………42
6.8. Premature Closure of the Study………………………………………………………..42 
6.9. Record Retention………………………………………………………………………...43
7.  References…………………………………………………………………………………….44
8.  Appendices……………………………………………………………………………………49
8.1. Study Flow Chart………………………………………………………………………..49
8.2. Body Surface Area and Creatinine Clearance Calculations………………………..50 
8.3. Declaration of Helsinki………………………………………………………………….51
8.4. FACT/GOG-Neurotoxicity Questionnaire, Version 4.0………………………….     55
8.5. New York Heart Association Classification……………………………………………56
8.6. HRCT Security and Interpretation……………………………………………………..57
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ABBREVIATION LIST
Abbreviation
Definition
C
M 
20S 
AE 
ANC 
BSA
cm 
CTCAE
dL 
DNA 
FDA 
FVC 
GCP 
GLP
ht 
HSCT 
ICH 
IEC 
IND 
IRB 
IV
kg 
Ki 
lbs 
m2 
mg 
min 
ml 
mm3
MMF
mmol 
NF-B
ng 
nM 
PFT
PPAR- 
SAE
SSc 
TGF-1 
US 
USP
wt
degrees Celsius 
micromolar
20S proteasome subunit 
adverse event
absolute neutrophil count 
body surface area 
centimeter
(NCI) Common Terminology Criteria for Adverse Events 
deciliter
deoxyribonucleic acid
Food and Drug Administration 
Forced Vital Capaciy
Good Clinical Practice 
Good Laboratory Practice 
height
Hematopoietic Stem cell transplantation 
International Conference on Harmonisation 
Independent Ethics Committee 
Investigational New Drug
Institutional Review Board 
intravenous
kilogram
inhibitory constant 
pounds
square meters 
milligram 
minute 
milliliter
cubic millimeters 
Mycophenolate mofetil 
millimole
nuclear factor-B 
nanogram 
nanomole
Pulmonary Function Testing
Peroxisome proliferator-activated receptor-gamma 
serious adverse event
Systemic Sclerosis
Transforming Growth Factor-beta1 
United States
United States Pharmacopeia 
weight
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1.0 BACKGROUND AND STUDY RATIONALE
1.1. Overview of Disease
Prevalence estimates for systemic sclerosis (i.e. scleroderma) vary from 138 to 660 per million 
population. There two distinct subtypes, diffuse cutaneous and limited cutaneous though both 
have multi-organ manifestations. Pulmonary disease is now the most common cause of 
mortality. Overall 30%-40% of patients will develop pulmonary fibrosis, usually within 2-4 years 
of diagnosis. Scleroderma lung disease is marked by loss of the alveolar capillary units which 
can be quantified on pulmonary function testing as a fall in the total lung capacity (TLC) and 
the diffusing capacity for carbon monoxide (DLCO). Radiologically scleroderma lung disease is 
marked by increased interstitial infiltrates which can progress to honeycombing at end-stage.
Lung Fibrosis-Abnormal Lung Repair
While the etiology and pathogenesis of SSc remain incompletely understood, the initial insult is 
likely to be vascular. After injury, the recovery of normal tissue function can be prevented or 
delayed by the development of fibrosis (6). Fibroblast activation in response to alveolar 
epithelial injury is required for tissue repair and recovery of lung function (7), but if not properly 
regulated may also lead to impaired compliance and gas exchange, and pulmonary fibrosis. In 
animal models, investigators have reported that activation of the cytokine Transforming growth 
factor-beta (TGF-) is required and sufficient for the development of fibrosis in the lung and 
other organs (8). In the lung the intratracheal administration of bleomycin results in acute lung 
injury followed by TGF- dependent lung fibrosis (8). In addition to in vitro and animal data 
there is also compelling human data on the importance of TGF- in tissue fibrosis. Gene 
expression analysis of tissue obtained by lung and skin biopsies showed upregulation of many 
TGF- regulated genes(9,10). In addition we and others have detected active TGF- in the 
alveolar fluid of pulmonary fibrosis patients which is transcriptionally active (11).
Active TGF- binds to its plasma membrane receptors inducing signaling cascades that 
transcriptionally 
regulate 
myofibrobast 
differentiation, 
collagen 
expression 
and 
endothelial/epithelial to mesenchymal cell transition (12). Full expression of TGF- mediated 
gene expression requires canonical smad and non-smad pathways (12). The transcriptional 
program activated by TGF- is therefore an attractive therapeutic target for the prevention of 
organ fibrosis after injury (8,13,14).
TGF-Β IN TISSUE REPAIR
Fibroblast activation after lung  injury is 
characterized by elevations of the pro- 
fibrotic cytokine TGF- (15,16) .   TGF-
interstitium in a latent form. Upon injury 
to the epithelium or endothelium, TGF-β 
is converted from a latent to active form 
(17-21) and binds to one of a family of 
TGF-β receptors present on the cell 
surface, activating multiple downstream 
signaling cascades. Binding of TGF-β 
with the ALK5 receptor has been shown 
to be required for the development of 
fibrosis in multiple models. Activation of 
the 
ALK5 
receptor 
induces 
the 
phosphorylation of one of the small 
mothers       against       decapentaplegic
Plasma Membrane
RIII
RII
RI
Smad 6 or 7
Activated
Smad 2 or 3
Smad 2 or 3
Gene Transcription
Smad 4
Nucleus
Active TGF-β
Figure 1. Signaling by TGF-β.
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(Smads) (Smad2). Smad2 forms a complex with other Smad proteins, which translocates to the 
nucleus where it interacts with transcriptional co-activators or repressors to regulate gene 
transcription (Figure 1).
The consequences of Smad mediated transcription are cell type specific. In resident lung 
fibroblasts or fibroblasts recruited from circulating fibrocytes, TGF-β stimulates proliferation and 
transformation to myoyfibroblasts (22-24). Myofibroblasts are specialized fibroblasts important 
in tissue repair and fibrosis that express alpha-smooth muscle actin (α-SMA), secrete 
increased extracellular matrix and release fibrogenic cytokines (i.e. connective tissue derived 
growth factor (CTGF), platelet derived growth factor (PDGF) and others). In addition, 
stimulation of myofibroblasts with TGF-β stimulates them to release active TGF-β, amplifying 
the fibrotic signal (24). Myofibroblasts have been reported in biopsy specimens obtained from 
patients with ARDS and patients with idiopathic pulmonary fibrosis. In epithelial cells, Smad 
signaling can induce apoptosis or a transition to a mesenchymal phenotype (EMT) (25,26). In 
rodent models of lung fibrosis, preventing the activation of TGF-β, blocking the TGF-β receptor, 
inhibiting Smad activation in response to receptor binding and inhibiting Smad dependent gene 
transcription have all been shown to attenuate lung fibrosis in response to bleomycin (8). A 
similar requirement for TGF-β signaling has been observed in lung fibrosis that develops in 
response to ionizing radiation and asbestos (27). TGF-β signaling has also been shown to 
play a critical role in the fibrosis that develops in the liver, skin, gut and kidney in response to 
different fibrogenic stimuli(13). Collectively, this has led investigators to hypothesize that the 
activation of TGF-β serves as a “fibrotic switch” that is turned on in response to injury and 
turned off after repair. Excessive fibrosis likely results from unregulated activation of TGF-β or 
from its failed downregulation after repair of injury.
Smad-dependent pathways are required for the normal regulation of tissue regeneration, 
inflammation and fibrosis. As a result, strategies that completely inhibit Smad signaling have 
been associated with significant toxicity. To overcome these difficulties, investigators have 
focused on pathways that modulate the intensity of Smad signaling or act independent of the 
Smad pathway in mediating the full TGF-β mediated cellular response (28-30). For example, 
activation of the mitogen-activated protein kinase (MAPK) pathways including p38 (28), 
extracellular signal-regulated protein kinase (ERK) (30), or the c-Jun N-terminal kinase (JNK)
(31) is often required for effective TGF-β signaling (32). Imatinib (Gleevec) is an example of a 
small molecule designed to inhibit Smad-independent signaling by TGF-β. Imatinib inhibits 
TGF-β-induced activation of the tyrosine kinase, c-Abelson (c-Abl), which is required for 
extracellular matrix expression in fibroblasts. The administration of imatinib to mice was shown 
to prevent pulmonary fibrosis in the bleomycin model, but only when the drug was administered 
before the administration of bleomycin (33,34).
PPAR- INHIBITS TGF-Β1 MEDIATED SIGNALING/FIBROSIS
Peroxisome proliferator-activated receptor-gamma (PPAR-γ) is a nuclear hormone receptor 
and transcription factor that is essential for normal adipogenesis and glucose homeostasis. 
PPAR-γ exists as two isoforms in human cells that are splice variants of a single gene.  PPAR-
γ1 is ubiquitously expressed and plays an important role in glucose metabolism. PPAR-γ2 is 
expressed only in adipocytes where it functions as a master switch in adipocyte development. 
Endogenous lipids and eicosanoids such as 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) act 
as natural PPAR-γ ligands. Activation of PPAR-γ can also be induced by thiazolidinedione anti- 
diabetic drugs such as rosiglitazone.
We have previously reported that in normal skin fibroblasts, PPAR-γ ligands block the 
upregulation of collagen synthesis and α-SMA expression induced by TGF-β (35). Ectopic
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Figure 2. The targeting of proteins for 
degradation by the ubiquitin- 
proteasome system. From reference 
((38)).
PPAR- elicited a similar response in these cells even in the absence of PPAR- ligand. 
Recently they reported that mouse embryonic fibroblasts (MEFs) lacking PPAR- displayed 
substantially elevated basal levels of collagen gene expression. Collagen gene expression 
persisted despite the administration of PPAR- ligands, but was normalized by the expression 
of ectopic PPAR-. In addition, PPAR- null MEFs had increased TGF-β production and 
elevated levels of expression of the type I TGF-β receptor (TβRI). Furthermore, PPAR- null 
MEFs showed constitutive activation of endogenous Smad2/3 in the absence of PPAR- 
exogenously added ligand (36). Together, these results suggest that cellular PPAR- plays an 
important physiological role in negatively modulating the intensity of intracellular TGF-β 
signaling and target gene expression. Further, PPAR- agonists, if administered prior to 
bleomycin instillation, have been shown to be protective against pulmonary fibrosis (37).
PROTEASOMAL DEGRADATION OF PROTEINS
Since 
its 
original 
description 
by 
Dr. 
Aaron 
Ciechanover 
and 
colleagues, 
the 
ubiquitin/proteasome system has emerged as a key pathway which defines cellular protein 
turnover and consequently the levels and activity of numerous intracellular proteins. Proteins 
are targeted for degradation by the covalent linkage of ubiquitin to a lysine residue in the target 
protein. Ubiquitin is a small, ubiquitously expressed protein that is highly conserved throughout 
evolution. In most cases, ubiquitin is linked to the substrate protein through an isopeptide bond 
between the ε-amino group of a lysine in the target protein and the COOH-terminal glycine of 
ubiquitin. Cycles of these reactions link additional ubiquitins to lysines within the previously 
added ubiquitin.
The conjugation of ubiquitin to protein substrates 
involves a series of hierarchically organized steps 
(Figure 2). An E1 ubiquitin-activating enzyme that is 
present in all mammalian cells catalyzes the 
formation of an E1 ubiquitin thioester adduct with the 
COOH-terminal glycine of ubiquitin in a reaction that 
requires ATP. The E1 enzyme transfers the ubiquitin 
to members of the E2 ubiquitin-carrier protein family 
(also called ubiquitin-conjugating enzymes). For the 
majority of proteins the transfer of ubiquitin from the 
E2 ligase to the protein targeted for degradation 
requires the participation of an E3 ubiquitin ligase. 
The E3 ligases are a large class of a structurally 
diverse family of proteins that may number in the 
hundreds in humans (38). They provide selectivity to
the ubiquitin process by serving as docking proteins that bring the substrate protein and the E2 
carrier protein with activated ubiquitin together. In some instances, accessory proteins also 
interact with E3 ubiquitin ligases to facilitate substrate recognition.
Signaling through TGF- is known to be regulated by the ubiquitin conjugating system. HECT 
domain E3 ligases, facilitate the degradation of receptor regulated Smads 2,3 and some of the 
proteins that comprise the TGF- receptor. The RING finger E3 ligase Arkadia is activated 
upon binding to Smad7 and targets it and the transcriptional repressors SnoN and c-Ski for 
degradation. By removing these three independent inhibitors of Smad transcription, Arkadia 
enhances TGF- signaling.
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The 26S Proteasome
In addition to its role in removing damaged proteins, the 
ubiquitin/proteasome system has been shown to play a critical role 
in the regulation of proteins that affect inflammatory processes, cell 
growth, and differentiation. The proteasome is located both in the 
cytoplasm and the nucleus (38). It has a barrel-like structure that is 
capped at each end by regulatory 19S proteins (Figure 3). The 
barrel moiety or core 20S particle has both a scaffold-like and 
proteinase functions. The active site threonine residues whose 
hydroxyl groups function as the catalytic nucleophils have three 
distinct cleavage preferences termed: chymotryptic, tryptic, and 
caspase. Inhibitors of the proteasome can bind to one of more of 
these sites to inhibit enzymatic function. The regulatory 19S 
complex at each end of the barrel functions to recognize, bind and 
unwind proteins prior to degradation. The 20S core and the 19S 
regulatory units are collectively referred to as the 26S proteasome.
Inhibiting   the   activity   of   the   proteasome   prevents   substrate
degradation which leads to modulation of associated proteins that are involved in disease 
states. Inhibition of these “activated” proteins (e.g., transcription factors such as nuclear factor- 
κB (NF-κB) or HIF) can modulate molecular pathways, and the resulting phenotype in disease 
models. Proteasomal inhibitors have been shown to ameliorate liver steatosis/fibrosis (39,40), 
myelofibrosis (41) cardiac fibrosis (42) and renal fibrosis (43) in animal models. The 
mechanism by which proteasomal inhibition protects against injury/fibrosis is not known; 
investigators have proposed that proteasomal inhibition might prevent TGF-β1 activation (41), 
the expression of TGF-β regulated fibrotic genes (44) or an increase in fibroblast apoptosis 
(40).
Bortezomib is a modified dipeptidyl boronic acid that 
intercalates into an active site of the proteasome to 
specifically and reversibly inhibit the chymotrypsin-like 
activity of the 26S proteasome in mammalian cells (Figure 
4). It is the first proteasomal inhibitor approved by the FDA 
for clinical use for the treatment of multiple myeloma, 
mantle cell lymphoma and other malignancies.
TGF-, PPAR- and Ubiquitin/Proteasomal system   Little 
is known regarding the proteasomal degradation of 
PPAR-γ.  We  have  data  that  bortezomib  inhibits  TGF-β 
mediated gene expression, prevents PPAR-γ degradation 
and   promotes   normal   healing   by   protecting   against 
bleomycin pulmonary and skin fibrosis when begun 7 or 
days after bleomycin instillation. We also have data that 
BAL   fluid   from   pulmonary   fibrosis
patients   induces
profibrotic gene expression which is inhibited by bortezomib. In addition we have shown that 
bortezomib inhibits profibrotic  gene expression  in lung  and  skin  fibroblasts obtained  from 
pulmonary and skin fibrosis patients respectively.
Figure 3. The 26S 
proteasome.
Bortezomib
Figure 4. Binding of  bortezomib 
with a  catalytic domain in the 26s 
proteasome to reversibly inhibit its 
chymotrypsin like activity.
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1.2 BORTEZOMIB (BORTEZOMIB FOR INJECTION)
1.2.1 Scientific Background
Bortezomib for Injection is a small molecule proteasome inhibitor developed by Millennium 
Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human malignancies. Bortezomib 
is currently approved by the United States Food and Drug Administration (US FDA) 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, bortezomib affects multiple signaling 
pathways. The anti-neoplastic effect of bortezomib likely involves several distinct mechanisms, 
including inhibition of cell growth and survival pathways, induction of apoptosis, and inhibition 
of expression of genes that control cellular adhesion, migration and angiogenesis. Thus, the 
mechanisms by which bortezomib elicits its antitumor activity may vary among tumor types, 
and the extent to which each affected pathway is critical to the inhibition of tumor growth could 
also differ. Bortezomib has a novel pattern of cytotoxicity in National Cancer Institute (NCI) 
in vitro and in vivo assays (45). In addition, bortezomib has cytotoxic activity in a variety of 
xenograft tumor models, both as a single agent and in combination with chemotherapy and 
radiation (46,47). Notably, bortezomib induces apoptosis in cells that over express bcl-2, a 
genetic trait that confers unregulated growth and resistance to conventional chemotherapeutics 
(McConkey et al., 1999).
Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear factor
B (NF-B) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct 
apoptotic effect, and possibly anti-angiogenic and other effects (48).
1.2.2 Nonclinical Pharmacology
Pharmacokinetic (PK) and pharmacodynamic studies were conducted in the rat and 
cynomolgus monkey. Upon intravenous (IV) bolus administration, bortezomib displays a rapid 
distribution phase (t½ <10 minutes) followed by a longer elimination phase (t½ 5–15 hours). 
Bortezomib has a large volume of distribution (range 5–50 L/kg). The plasma PK profile is well 
described by a 2-compartment model.
The pharmacodynamic action of bortezomib is well established and can be measured through 
an ex vivo assay (20S proteasome activity) (49). This assay was used to determine the 
duration of drug effect in lieu of the PK data in the early preclinical toxicology studies as well as 
to set a guide for dose escalation in humans. Following dosing with bortezomib in the rat and 
cynomolgus monkey, proteasome inhibition in peripheral blood had a half-life less than 24 
hours, with proteasome activity returning to pretreatment baseline within 24 hours in monkey 
and within 48 to 72 hours in rat after a single dose of bortezomib. Further, intermittent but high 
inhibition (>70%) of proteasome activity was better tolerated than sustained inhibition. Thus, a 
twice-weekly clinical dosing regimen was chosen in order to allow return of proteasome activity 
towards baseline between dose administrations.
1.2.3 Nonclinical Toxicity
Single-dose IV toxicity studies were conducted with bortezomib in the mouse, rat, dog, and 
monkey to establish the single-dose maximum tolerated dose (MTD). The MTDs were 0.25 
mg/kg (1.5 mg/m2) and 0.067 mg/kg (0.8 mg/m2) in the 2 most sensitive species, rat and 
monkey, respectively.
Repeat-dose multi-cycle toxicity studies of 3 and 6 months in the rat and 9 months in the 
monkey, each with 8-week recovery  periods,  were  conducted  to characterize the chronic
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toxicity of bortezomib when administered by the clinical route and regimen of administration. 
The MTD in the 6-month rat study was 0.10 mg/kg (0.6 mg/m2) and the key target organs were 
the gastrointestinal (GI) tract, hematopoietic and lymphoid systems. The MTD in the 9-month 
monkey study was 0.05 mg/kg (0.6 mg/m2) and the key target organs were the GI tract, 
hematopoietic and lymphoid systems, peripheral nervous system, and kidney. Full or partial 
reversibility was observed for each of the toxicities described to date.
In general, the nature of the toxicity of bortezomib is similar across species, and target organs 
of toxicity in animals have been largely predictive of human toxicity. The toxicity of bortezomib 
in animals is characterized by a steep dose-response with mortality seen at dosages above the 
MTD. The cause of death at acutely lethal dosages is considered to be related to indirect 
cardiovascular (CV) effects of hypotension and vascular changes with secondary bradycardia 
and the cause of death in long-term studies has been attributed to GI or hematologic toxicity. 
The pharmacologic effects of bortezomib on the CV system have been extensively 
characterized and have demonstrated that indirect effects on CV function occur only at acutely 
lethal dosages and are abrogated by routine supportive care.
1.2.4 Clinical Pharmacokinetics and Pharmacodynamics
The clinical pharmacology characterization of bortezomib has been determined from phase 1 
studies in subjects with solid tumors and hematological malignancies, and  confirmed  in 
phase 2 studies in subjects with multiple myeloma.
Bortezomib demonstrates multi-compartmental pharmacokinetics. Following intravenous 
administration of 1.0 mg/m2 and 1.3 mg/m2 dose, the mean first-dose maximum observed 
plasma concentrations of bortezomib were 57 and 112 ng/mL, respectively in 11 patients with 
multiple myeloma and creatinine clearance values >50 mL/min participating in a 
pharmacokinetics 
study. 
In 
subsequent 
doses, 
mean 
maximum 
observed 
plasma 
concentrations ranged from 67 to 106 ng/mL for the 1.0 mg/m2 dose and 89 to 120 ng/mL for 
the 1.3 mg/m2 dose. The mean elimination half-life of bortezomib upon multiple dosing ranged 
from 40 to 193 hours. Bortezomib is eliminated more rapidly following the first dose. Mean 
Total Body Clearances were 102 and 112 L/h following the first dose for doses of 1.0 mg/m2 
and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for 
doses of 1.0 and 1.3 mg/m2, respectively. Clinical experience has shown that the change in 
clearance does not result in overt toxicity from accumulation in this multidose regimen in 
humans.
In subjects with advanced malignancies, the maximum pharmacodynamic effect (inhibition of 
20S activity) occurred within 1-hour post dose. At the therapeutic dose of 1.3 mg/m2  in 
subjects with multiple myeloma, the mean proteasome inhibition at 1-hour post dose was 
approximately 61%.
The time course of proteasome inhibition in subjects is characterized by maximum inhibition 
observed within the first hour after administration, followed by partial recovery of proteasome 
activity over the next 6 to 24 hours to within 50% of the pretreatment activity. On the Day 1, 4, 
8, and 11 schedule, variable (10%–30%) levels of proteasome inhibition have been observed 
at next scheduled dosing. In theory, this advantage allows cells to recover proteasome activity 
for normal cellular housekeeping functions between doses.
The relationship between bortezomib plasma concentrations and proteasome inhibition can be 
described by a maximum effect (Emax) model. The Emax curve is initially very steep, with small 
changes in plasma bortezomib concentration over the range of 0.5 to 2.0 ng/mL relating to 
large increases in the percent inhibition (0–60%).  After that, a plateau occurs where marginal
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increases of proteasome inhibition are observed in spite of large changes in plasma 
bortezomib concentrations.
1.2.5 Clinical Experience
It is estimated that as of August 31, 2006, more than 44,000 patients have been treated with 
bortezomib, including patients treated through Millennium-sponsored clinical trials, Investigator- 
Initiated Studies, the US NCI Cancer Therapy Evaluation Program (CTEP), and with 
commercially available drug. Bortezomib has been commercially available since 13 May 2003. 
The overall goal of the Millennium phase 1 program was to determine the MTD and dose- 
limiting toxicity (DLT) of bortezomib in a number of therapeutic settings involving subjects with 
various advanced malignancies. In a Phase I trial in patients with refractory hematologic 
malignancies, the MTD for a twice weekly for 4 weeks of a 42 day cycle was 1.04 mg/m2/dose, 
with DLTs of thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise (50). The 
toxicity was greatest during the third and fourth weeks of therapy. In the 3-week schedule of 
bortezomib monotherapy (4 doses, given on Days 1, 4, 8, and 11 of a 21-day treatment cycle), 
the DLT occurred at 1.56 mg/m2/dose (3 subjects with Grade 3 diarrhea and 1 with peripheral 
sensory neuropathy). Therefore, the MTD at this schedule was 1.3 mg/m2/dose. In a 35-day 
treatment cycle with 4 weekly doses of bortezomib monotherapy, the MTD was 1.6 mg/m2/dose 
and DLT included hypotension, tachycardia, diarrhea, and syncope.
In phase 1 clinical studies, 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 bortezomib in subjects with multiple myeloma were investigated in 
two phase 2 clinical studies, studies M34100-024 (subjects with first relapse) (51)and M34100- 
025 (subjects with second or greater relapse and refractory to their last prior therapy) (52). In 
M34100-025, 202 heavily pre-treated subjects with refractory multiple myeloma after at least 2 
previous treatments received bortezomib, 1.3 mg/m2 on Days 1, 4, 8, and 11 of a 21-day 
treatment cycle. The European Group for Blood and Marrow Transplant (EBMT) response 
criteria, as described by Blade (Blade et al., 1998) were utilized to determine disease 
response. CRs were observed in 4% of subjects, with an additional 6% of patients meeting all 
criteria for CR but having a positive immunofixation test. PR or better was observed in 27% of 
subjects, and the overall response rate (CR, PR and minor response [MR] combined) was 
35%. Seventy percent of subjects experienced stable disease or better.
The phase 3 study (M34101-039) (53), also referred to as the APEX study, was designed to 
determine whether bortezomib provided benefit (time to progression [TTP], response rate, and 
survival) to patients with relapsed or refractory MM relative to treatment with high-dose 
dexamethasone. The study was also designed to determine the safety and tolerability of 
bortezomib relative to high-dose dexamethasone, and whether treatment with bortezomibwas 
associated with superior clinical benefit and quality of life relative to high-dose dexamethasone. 
A total of 669 patients were enrolled and 663 patients received study drug (bortezomib: 331; 
dexamethasone: 332). Patients randomized to bortezomib received 1.3 mg/m2 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 bortezomib weekly on days 1, 8, 15, and 22 of a 5-week cycle 
for three cycles as maintenance therapy. Patients randomized to dexamethasone received oral 
dexamethasone 40 mg once daily on days 1 to 4, 9 to 12, and 17 to 20 of a 5-week cycle for up 
to four treatment cycles as induction therapy, followed by dexamethasone 40 mg once daily on 
days 1 to 4 followed of a 4-week cycle for five cycles as maintenance therapy. The European 
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
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TTP for the bortezomib arm. Median TTP was 6.2 months for the bortezomib arm and 3.5 
months for the dexamethasone arm (P<.0001). CR (complete response) + PR (partial 
response) was 38% with bortezomib vs. 18% with dexamethasone (P.0001). CR was 6% with 
bortezomib vs. 1% with dexamethasone (P<.0001). The CR + nCR rate was13% with 
bortezomib vs. 2% with dexamethasone. In patients who had received only one prior line of 
treatment (bortezomib: 132; dexamethasone: 119), CR + PR was 45% with bortezomib vs. 
26% with dexamethasone (P=.0035). With a median 8.3 months of follow-up, overall survival 
was significantly longer (P=.0013) for patients on the bortezomib arm vs. patients on the 
dexamethasone arm. The probability of survival at one year was 80% for the bortezomib arm 
vs. 66% for the dexamethasone arm, which represented a 41% decreased relative risk of death 
in the first year with bortezomib (P=.0005). In patients who had received only one prior line of 
treatment, the probability of survival at one year was 89% for the bortezomib arm vs. 72% for 
the dexamethasone arm, which represented a 61% decreased relative risk of death in the first 
year with bortezomib (P=.0098). Updated response rates and survival data were reported for 
M34101-039 (53). The updated CR (complete response) + PR (partial response) rate was 43% 
with bortezomib. The CR + nCR rate was 16% with bortezomib. With a median 22 months of 
follow-up, overall survival was  significantly  longer for  patients on the  bortezomib arm vs. 
patients on the dexamethasone arm. The median overall survival was 29.8 months (95% CI: 
23.2, not estimable) for the bortezomib arm vs 23.7 months (95% CI: 18.7, 29.1) for the 
dexamethasone arm (hazard ratio = 0.77, P= 0.0272). The probability of survival at one year 
was 80% for the bortezomib arm vs. vs 67% for the dexamethasone arm (P=0.0002).
Studies using bortezomib as monotherapy and in combination with other chemotherapy agents 
are continuing.
1.2.6 Potential Risks of bortezomib
To date, more than 100,000 patients have been treated with bortezomib in both clinical trials 
investigating its use in hematological malignancies and solid tumors, and in patients who were 
treated with commercially available bortezomib. Please see table 1 and section 5.5 of the 
bortezomib Investigators’ Brochure (IB, V17 Apr 2014) for the known anticipated risks of 
bortezomib and a consolidated table listing the approximate incidence of those risks.
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Table 1
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Table 1
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Table 1
Other medical events of interest that are considered not causally related to BORTEZOMIB 
include hepatic failure and QT prolongation. Fatal outcomes have been reported. Women of 
childbearing potential should avoid becoming pregnant while being treated with BORTEZOMIB. 
Genotoxicity testing has shown that bortezomib is negative in the in vitro Ames assay and in 
the in vivo micronucleus assay, but it is a clastogen in the in vitro chromosomal aberration 
assay.
1.3 STUDY RATIONALE AND SELECTION OF DRUG DOSES
The study is being conducted to establish the safety and tolerability of bortezomib in SSc 
patients at high risk for pulmonary disease progression. In addition the study will examine the 
effect of bortezomib on the rate of FVC decline (a physiologic parameter closely associated 
with disease outcome) and other clinical parameters. In addition we will also measure the effect 
of bortezomib on biomarkers associated with fibroblast activation. If successful, the study will 
provide the rationale for a multi-center placebo controlled trial to test the efficacy of bortezomib 
in SSc patients at high risk for progressive pulmonary disease.
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Rationale for drug dosing: The standard dose of bortezomib in multiple myeloma is 1.3 mg/m2. 
In our mouse bleomycin experiments we observed antifibrotic effects at this dose (proportional 
to body surface area of a mouse) as well as doses up to ten fold lower. In addition we detected 
efficacy when given weekly for two weeks out of four. In a separate study we have found that 
bortezomib at a dose of 1.3mg/m2 weekly is well tolerated in patients with pulmonary GVHD, a 
non-oncologic population. Thus, we propose to test a dose of bortezomib 1.3 mg/m2. We will 
also administer bortezomib for 2 weeks out of a 4 week cycle and the cycle will be repeated 3 
times.  We will then administer bortezomib for 1 week out of a 4 week cycle and the cycle will be 
repeated for 3 cycles.
Benefits
In SSc patients with progressive pulmonary disease, mortality is substantial and most patients 
die from their pulmonary disease. Thus strategies effective at preventing progressive fibrosis 
are likely to have to have salutary effects on mortality. Bortezomib is an FDA approved therapy 
for the treatment of multiple myeloma and other malignancies. We have data that bortezomib 
inhibits TGF- signaling in vitro and promotes normal repair and prevents against lung fibrosis 
in the TGF- mediated intratracheal bleomycin mouse model as well as in a mouse model for 
skin fibrosis (54). This is consistent with other data in the literature that proteasomal inhibition 
can prevent the development of fibrosis (41,55). Further there are multiple reports on the 
efficacy of bortezomib in ameliorating cGVHD in patients after allogeneic HSCT for multiple 
myeloma (56,57). Bortezomib was also well tolerated in the large clinical trials of multiple 
myeloma patients with neuropathy and thrombocytopenia the primary adverse events (53). No 
pulmonary toxicities were reported in these studies.
Risk
Studies in monkeys have shown that acute administration of bortezomib at twice the 
recommended clinical dose resulted in cardiovascular collapse and death 12-14 hours after 
administration. Doses > 1.3 mg/m2  induced dose-proportional changes in cardiac parameters. 
bortezomib distributes to most tissues in the body except for the CNS, testes and eyes. Toxicity 
observed with chronic administration at dose and schedule used in multiple myeloma patients,
1.3 mg/m2, twice a week for 2 weeks followed by 1 week rest, included peripheral neuropathy, 
thrombocytopenia, anemia, GI, neurologic and lymphoid system toxicities.
There are, however, reports of patients who developed pulmonary toxicity following bortezomib 
administration (58) on a twice weekly basis. The vast majority of these patients were in Japan. 
At the time of the earliest report, bortezomib was not approved in Japan and was imported from 
abroad for administration. In addition no consideration was given to patient’s performance 
status or chest x-ray findings and acute infection was not excluded. After this report was 
published, it was recommended that bortezomib be administered only to patients with a good 
performance status and no evidence of infection. Implementation of these guidelines has led, 
in 2 different studies (59), to a 10-fold reduction in incidence of pulmonary complications, 
including a post-marketing surveillance cohort of 666 patients(60). Based in part on these 
studies, bortezomib was approved in Japan in 2006. Though there are sporadic case reports 
of bortezomib induced pulmonary toxicity from elsewhere (61,62), there are no reports 
suggesting the high rate of bortezomib induced pulmonary toxicity seen in Japan and 
pulmonary toxicity was not reported in the pivotal US phase 2 study(52). In addition we have 
pulmonary function data on 73 patients after induction treatment with bortezomib comprising 
12-24 doses and have found no unexpected abnormalities of pulmonary function (see 
appendix). These patients have undergone high-dose chemotherapy with HSCT subsequently 
without any unanticipated lung problems. We also have anecdotal experience of administering 
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bortezomib to 6 critically ill multiple myeloma patients in the intensive care unit with no specific
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pulmonary adverse effects. Finally based upon our experience and recent data from an Italian 
study (63)in myeloma, it is expected that administration of bortezomib for 2 weeks out of 4 for 
3 cycles and then 1 week out of 4 for 3 cycles will be associated with a substantial 
reduction in all types of toxicity.
1.4
Mycophenolate Mofetil (MMF)
ADMINISTRATION ROUTE: ORAL
Dosing unit: Capsules containing 500 mg MMF. 
Dosing: up to 1.5 g twice daily for 24 weeks:
Subjects will be on a stable dose of MMF for at least 8 weeks prior to enrolling in the study. 
Dosing may be held or down-titrated at any time if indicated by study criteria for safety and/or 
tolerability. Participants will continue their MMF for the duration of the study of 24 weeks.
2.0     STUDY OBJECTIVES
2.1
Primary Objective

To assess safety and tolerability of bortezomib in combination with MMF in 
System Sclerosis (SSc) patients at high risk of progression of pulmonary 
disease

To assess the effect of bortezomib in combination with MMF on lung function in 
SSc patients at high risk of progression of pulmonary disease
2.2
Secondary objectives

To assess the effect of bortezomib in combination with MMF on Quality of Life 
and respiratory symptom scores in SSc patients at high risk of progression of 
pulmonary disease

To assess the effect of bortezomib in combination with MMF on skin fibrosis in 
System Sclerosis (SSc) patients at high risk of progression of pulmonary 
disease
2.3
Exploratory objective

To assess the effect of bortezomib in combination with MMF on serum 
biomarkers

To assess the effect of bortezomib in combination with MMF on aberrant gene 
expression in skin biopsies and from SSc patients at high risk for disease 
progression
3.0     INVESTIGATIONAL PLAN
3.1 Overall Design and Plan of the Study
This is a pilot randomized double blind clinical trial in which bortezomib or placebo is 
added to MMF in System Sclerosis (SSc) patients at high risk of progression of 
pulmonary disease (defined below).
3.2 Selection of Patients
The total number of patients to be enrolled is 30.
Enrollment is defined as the first day of bortezomib or placebo (i.e. day 1 of cycle 1).
3.2.1
Inclusion Criteria
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1.
Meet established criteria for diffuse or limited SSc and evidence of 
pulmonary at high risk of progression with or without progressive skin 
disease.
i.
Definition
includes
subjects
who
meet
the
ACR
criteria
for 
scleroderma
ii.
High Risk of disease progression (see rationale) will be defined as 
follows
1.
If SSc diagnosis < 36 months then if any of the following are 
true:
a.
FVC <70% predicted
or
b. HRCT Fibmax >3
or
c.
FVC < 85% and MRSS increase of 5 over 6 months
2.
Regardless of disease duration
a.
Fall in FVC > 10% over the preceding 12 months or 
less in the absence of prior therapy or another 
identified causative process as assessed by the 
primary scleroderma physician
b. Fall in FVC > 10% over 12 months on at least 6 
months of prior therapy
2.
Age > 18 years
3.
Ability to give informed consent.
4.
Willingness to discontinue present therapy for the duration of the study
5.
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.
6.
Male subject agrees to use an acceptable method for contraception for the 
duration of the study.
7.
No evidence of acute infection 
8.  ANC >1000
9.
Platelets >75,000
10. Stable dose of MMF at least 8 weeks prior to enrollment
3.2.2  Exclusion Criteria
1.
Inability to give informed consent or comply with protocol procedures
2.
FVC < 40% or DLCO <30% predicted
3.
Patient  has  a  platelet  count  of  less  than  50,000  within  14 days  before 
enrollment.
4.
Patient has an absolute neutrophil count of less 1000 within 14 days before 
enrollment.
5.
Patient has a calculated or measured creatinine clearance of < 20 ml/minute 
within 14 days before enrollment.
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6.
Patient has  Grade 2 peripheral neuropathy by history within 14 days before 
enrollment.
7.
Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled 
angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic 
evidence of acute ischemia or active conduction system abnormalities. Prior to 
study entry, any ECG abnormality at Screening has to be documented by the 
investigator as not medically relevant.
8.
Patient has hypersensitivity to bortezomib, boron or mannitol.
9.
Female subject is pregnant or breast-feeding. Confirmation that the subject is 
not pregnant must be established by a negative serum -human chorionic 
gonadotropin (-hCG) pregnancy test result obtained during screening. 
Pregnancy testing is not required for post-menopausal or surgically sterilized 
women.
10.Patient has received other investigational drugs within 4 weeks before 
enrollment
11.Serious medical co-morbidity which in the opinion of the investigator makes 
participation in the study too high risk
12.Psychiatric illness likely to interfere with participation in this clinical study.
3.3STUDY TREATMENTS
3.3.1 CLINICAL TRIAL MATERIALS
Bortezomib for Injection is a sterile lyophilized powder for reconstitution and is 
supplied in vials containing Bortezomib and mannitol at a 1:10 ratio. For 
example, vials containing 3.5 mg of Bortezomib contain 35 mg of mannitol. MMF 
will be purchased as capsules.
Preparation, Handling and Storage of Drugs 
Bortezomib
Vials containing lyophilized BORTEZOMIB for Injection should be stored 
according to the label requirements. For the United States, store at USP 
Controlled Room Temperature which is 25ºC (77ºF); excursions permitted from 
15 to 30ºC (59 to 86ºF). For Europe, do not store above 30ºC (86ºF). To date, 
stability data indicate that the lyophilized drug product is stable for at least 18 
months when stored under the recommended conditions. Stability studies are 
ongoing, and Millennium Pharmaceuticals, Inc. will notify the investigator should 
this information be revised during the conduct of the study.
Bortezomib is cytotoxic. As with all cytotoxic drugs, caution is required when 
preparing and handling Bortezomib solutions.  Cytotoxic drugs should only be 
handled by staff specially trained in the safe handling of such preparations. The 
use of gloves and other appropriate protective clothing is recommended. In 
case of skin contact, wash the affected area immediately and thoroughly with 
soap and water for at least 15 minutes.  If product contacts eye, immediately 
flush eye thoroughly with water for at least 15 minutes. Always contact a 
physician after any form of body contact. All materials that have been used for 
preparation should be disposed of according to standard practices. A log must 
be kept of all disposed materials.
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Drug is available in sterile, single use vials containing 3.5 mg of Bortezomib. 
Each vial of Bortezomib for Injection should be reconstituted under a laminar flow 
biological cabinet (hood) within eight hours before dosing with 3.5 mL of normal 
(0.9%) saline, Sodium Chloride Injection USP, so that the reconstituted solution 
contains Bortezomib at a concentration of 1 mg/mL. Prior to reconstitution the 
vials should remain in the cartons to protect them from light. Dissolution is 
completed in approximately 10 seconds. The reconstituted solution is clear and 
colorless, with a final pH of 5 to 6. Reconstituted Bortezomib should be 
administered promptly and in no case more than 8 hours after reconstitution. All 
materials that have been used for preparation should be disposed of according to 
standard practices. A log must be kept of all disposed materials.
MMF
MMF will be distributed to study subjects in a bottle from their specific 
pharmacy. Subjects are responsible for the cost of the MMF.
Drug administration and dosage schedule
Bortezomib, 1.3 mg/m2 by subcutaneous injection or intravenously (only done if 
subcutaneous injection is not possible) once a week x 2 weeks for 3 cycles and 
then once a week for 3 cycles.
MMF 1.5 g twice a day orally.  
Bortezomib is being provided by Millennium Pharmaceuticals at no cost to the 
subjects and Northwestern University is receiving no monetary compensation form 
Millennium Pharmaceuticals.
Bortezomib or Normal Saline (placebo) Administration
Drug will be administered only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s). Patients may be treated on an out- 
patient basis, if possible. 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 patient experiences a notable change in weight (e.g. loss or gain of
8 lbs or 3.6 kg) within a cycle, as determined by an unscheduled weight 
assessment, then the patient’s dose should be recalculated at that time.
The appropriate amount of Bortezomib will be drawn from the injection vial and 
administered by subcutaneous injection.  The intent is for all subjects to receive 
the medication subcutaneously, but if that is not possible it will be 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.
MMF will be prescribed to patients by their primary care physician. The research 
subjects will be responsible for filling their prescription and purchasing the MMF 
from their local pharmacy.  Subjects will take the medication at home on their own. 
Each subject will record their use in a diary and bring it at their research visits.
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3.3.2 DOSE MODIFICATION AND DELAY
Bortezomib
Dose escalation will not be allowed in any patient, and there must be at least 1 
week between each dose of bortezomib. Dosing will be modified in patients with
evidence of moderate or severe hepatic impairment.  Before each drug dose, 
the patient will be evaluated for possible toxicities that may have occurred after 
the previous dose(s).All previously established or new toxicities observed 
any time, with the exception of neuropathic pain and peripheral sensory 
neuropathy, are to be managed as follows: If the patient experiences 
febrile neutropenia, a Grade 4 hematologic toxicity (including a platelet 
count <25  109/L) or any Grade 3 non-hematologic toxicity considered 
by the investigator to be related to bortezomib, then drug is to be held.
FOR NON-HEMATOLOGIC TOXICITIES, BORTEZOMIB IS TO BE HELD FOR UP TO 2 
WEEKS UNTIL THE TOXICITY RETURNS TO GRADE 1 OR BETTER. FOR 
HEMATOLOGIC TOXICITIES, BORTEZOMIB IS TO BE HELD FOR UP TO 2 WEEKS 
UNTIL THE PATIENT HAS A HEMOGLOBIN VALUE OF >8, PLATELET VALUE 
OF 20K AND NEUTROPHIL VALUE OF
>1000. Dose interruption or study discontinuation is not required for 
lymphopenia of any grade. If, after bortezomib has been held, the toxicity 
does not resolve, as defined above, then drug must be discontinued. If 
the toxicity resolves, as defined above, and bortezomib is to be restarted, 
the dose must be reduced by approximately 25% as follows: If the patient 
was receiving 0.7 mg/m2, reduce the dose to 0.5 mg/m2. Patients who 
experience bortezomib-related neuropathic pain and/or peripheral sensory 
neuropathy are to be managed as presented in Table 3.
Management of Patients with Bortezomib-Related Neuropathic Pain and/or 
Peripheral Sensory Neuropathy.
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The neurotoxicity-directed questionnaire (see section 8.4) is a useful tool for 
determining the presence and intensity of neuropathic pain and/or peripheral 
neuropathy from the patient’s perspective. Neuropathic symptoms are more 
prominent than abnormalities on the clinical examination. After the patient 
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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.
MMF
The toxicity profile for is MMF is well established as outlined below and drug 
discontinuation and/or dose modification will be managed by the Clinical 
Investigator (see below) using the following specific criteria.
Reasons for withholding the dose of study drug: The following abnormalities and 
laboratory tests require study drug discontinuation, either temporary (until 
normalization) or permanent, as indicated by the nature of the event, its severity 
and/or course of resolution upon discontinuation of therapy.

Allergic reaction associated with drug administration

WBC <2500, or < 1000 neutrophils

Platelet count < 20,000

Hemoglobin < 8.0 gm/dl

Documentation of gastrointestinal ulcer, bleeding or abdominal 
emergency

Pregnancy or initiation of breastfeeding

Intractable congestive heart failure

Serum creatinine > 2.0 mg/dl, or increase in serum creatinine of> 50% 
over baseline, or decrease of estimated GFR to < 45 mlIminl1.73 m2 (corrected) 
in the absence of other etiology

Ongoing infection whose management would be significantly 
compromised by continued drug-associated immunosuppression

Any adverse event felt by the investigator to be possibly or probably 
related to a study drug and of a clinical significant sufficient to warrant drug 
discontinuation
Management of drug dosing in response to specified toxicities. If any of the 
above toxicity occurs, the dose of study medication will be altered as follows:

Allergic reaction; pregnancy or breastfeeding; proven malignancy: Study 
drug will be stopped and subject withdrawn from study.

Bone Marrow Suppression: For leukopenia (WEC < 2500 and/or ANC < 
1000), thrombocytopenia « 20,000), or anemia (Hgb < 8 gm/dl) the study drug 
will be managed as follows:

Hold study drug until there is a stabilization of the hematologic 
abnormality at a value above the toxicity threshold levels ( Hgb > 8.0 
gm/dl , WBC > 2500, platelets > 20,000). In addition, if another cause for 
the reduction in hemoglobin is found (e.g., gastrointestinal bleeding), that 
cause should be appropriately treated and determined by the study 
physician to be stable before restarting on study drug.

Once threshold values are exceeded, the MMF will be reintroduced at by 
starting over at the lowest dose and the dose advanced every week as 
tolerated. At the clinical investigator discretion, after taking into account
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whether the study drug was likely or probably related to the adverse 
event, the final maintenance dose may be either the last regular dose 
taken by the patient or 500 mg/day less for MMF.

For hospitalizations, surgery or infections requiring antibiotics for which 
the immunosuppressive effects of the study drugs are determined by the 
investigator to likely complicate the clinical course: The study drug should be 
discontinued until the potential interaction with the medical condition in question 
has resolved. Once the patient is stable, the study drug can be restarted without 
dose modification.

Other severe or dangerous adverse events: For adverse events that are 
considered clinically serious by the investigator, the study drug will be managed 
as follows:

Hold study drug until there is resolution of the adverse event.
Once stable, the MMF will be reintroduced by starting over at the lowest dose 
with the dose advanced every week as tolerated. At the site investigator's 
discretion, after taking into account whether the study drug was likely or 
probably related to the adverse event, the final maintenance dose may be either 
the last regular dose taken by the patient or 500 mg/day less.
Follow-up should be every 1-2 weeks, as clinically indicated, until the 
investigator is satisfied that it is safe to return to the protocol-defined dosing 
schedule. In the event of repeat toxicity, the same cycle should be repeated 
except with the intention of achieving a maintenance dose equal to 1000 mg/day 
less.

For severe diarrhea, the MMF will be stopped and the subject will 
receive antidiarrheal medications until the diarrhea has resolved. The MMF wilI 
be reintroduced with a more gradual dose escalation and if necessary a goal 
dose of 1.5 grams to 2 grams per day.   If diarrhea recurs and the subject is 
intolerant of at least 1.5 grams to 2 grams of MMF per day, the subject will be 
removed from the study.
For less severe or dangerous adverse events (e.g., dyspepsia) not responding 
to concomitant medications: the study drugs are to be discontinued until the 
adverse event disappears, at the clinical discretion of the study physician. At 
that point the subject can be restarted at one-half of the original dose. The 
subject can return to the full dose of medications or one capsule less than the 
full dose, as clinically indicated, after 1 week at the half dose of medications. 
Discontinuation of study drug for unresolved toxicity: If the subject cannot 
resume study medication at some dose within one month of discontinuing, 
secondary to adverse or other events: the subject should be discontinued from 
the trial and the subject should complete the end of the study visits.
3.3.4 Treatment Assignment
Patients will be randomized to a 1:1 ratio to bortezomib or placebo for the study 
which will be added to MMF.
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3.3.5
Blinding Packaging and Labeling
Bortezomib will be supplied in vials as open-label stock. Both the box label and 
vial label will fulfill all requirements specified by governing regulations.
MMF will supplied in bottles. The bottle will fulfill all requirements specified by 
governing regulations.
3.3.6
CONCOMITANT TREATMENT
Required Concurrent Therapy
The following medications/supportive therapies are required during study 
participation, as applicable:

Patients will be administered their usual therapies at the discretion of the 
treating physician.

Acyclovir
Varicella zoster virus (VZV) reactivation is a common and serious adverse effect 
of  
bortezomib treatment.  Acyclovir 400 mg once daily has been shown to be 
sufficient  
to protect from VZV reactivation in patients treated with bortezomib.  All subjects 
will be required to take acyclovir  400 mg by mouth once per day after they have 
qualified for the study and prior to the first dose of bortezomib/placebo.  Subjects 
will be required to have the prescription written by their primary medical doctor or 
the primary investigator.  Subjects will be responsible for filling their prescription 
and purchasing the acyclovir from their local pharmacy.

Prohibited Concurrent Therapy

Any investigational agent other than Bortezomib.
3.3.7
Treatment Compliance
All drugs will be administered to eligible patients under the supervision of the 
investigator or identified sub-investigator(s). The pharmacist will maintain 
records of drug receipt (if applicable), drug preparation, and dispensing, 
including the applicable lot numbers, patients’ height, body weight, and body 
surface area (see section 8.2) and total drug administered in milliliters and 
milligrams and number of capsules. Any discrepancy between the calculated 
dose and dose administered and the reason for the discrepancy must be 
recorded in the source documents.
3.3.8
Concurrent Medications
Concurrent medications will be recorded at each visit. In addition, participants 
will be instructed to contact study physician in case their medication is changed 
by another physician. As this is a double-blind study, management of concurrent 
medications will be the same for all participants.
The following drugs have significant interactions with MMF: Hormonal 
Contraceptives, Antacids, Acyclovir, gancylovir, valcylorvir, Cholestyramine, 
Echinacea. Patients will be advised of these interactions and appropriate actions 
will be taken to prevent complications.
The following drugs are contraindicated: Azathioprine, Cyclcosporine, D- 
penicillamine, Methotrexate, Potab, Rituximab, Etanercept, Inflixamab, 
Adalimiumab. Corticosteroid use will be allowed if the dose is lower than equal 
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to 15mg of prednisone per day.
3.4 Duration of Treatment, Patient Participation and Study Procedures  
Once   enrolled   patients   randomized   to   bortezomib   will   receive   either   weekly 
subcutaneous injections or IV infusions of bortezomib/placebo for first 2 weeks of a 4 
week cycle for 12 weeks or 3 cycles and then once per week for 12 weeks or 3 
cycles and oral daily MMF. The 4 week cycle of bortezomib or SC/IV placebo will be 
repeated 6 times for a total of 24 weeks. The completion visit at the end of the 48 
weeks will serve as the primary endpoint visit. There will also be a visit 3 months after 
the primary endpoint visit.
3.4.1 SUMMARY OF STUDY VISITS
EVALUATIONS BY VISIT
Visit 0 Screening-SSc
Screening Protocol: After providing informed consent, patients will begin a staged 
screening protocol. Prospective patients will undergo a history and physical (H&P) 
and a Spirometry at a screening visit. Screen-eligible patients will be asked to 
undergo a high resolution computerized x-ray examination of the lungs (chest HRCT 
scan).  If the patient recently completed a chest HRCT scan (within the past 3 months), 
the scan may be considered in place of completing another scan for this study.  The 
thoracic HRCT will be assessed for study purposes and inclusion criteria within 
4 weeks of the screening visit by Dr. Hart. Patients meeting HRCT or 
alternative criteria will begin the enrollment visit. To be randomized the FVC from 
the screening and enrollment must be within 7% of each other to ensure a stable 
baseline. If not, a repeat FVC will be obtained within 7 days and if it agrees within 
7% of the FVC at screening, the patient can be randomized.

Medical Chart Review

H&P

Demographics

Vital signs

Assess AE’s and Concomitant medications

ECG

HRCT (If not done within 3 months of the visit for standard of care)

Spirometry

MRSS

Blood Work-CBC, Chemistries, urine dipstick pregnancy for women of child 
bearing potential

Distribute/collect MMF diary
Visit1 Enrollment-Study Day 1 (Cycle 1, Day 1)

Interim H&P (if applicable)

Full PFTs

Vital signs

Assess Ae’s and concomitant medications

MRSS and Hopkins Skin Score

Skin Biopsy (If consented)

Blood Work

QOL assessment and NU PRO

St. George’s and FACIT-dyspnea

6MW

Interim H&P
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
Blood Work/Serum for Biomarkers, urine dipstick pregnancy for women of 
child bearing potential

1st Dose of Randomized Bortezomib/ Placebo SC or IV Administration

Distribute/collect MMF Diary
Visits for Drug Administration Only (Visits 2-6, 8-&9)

Interim H&P(if applicable)Vital signs

Assess AE’s and concomitant medications

Toxicity Assessment for Neuropathy (Subjects will complete the FACT/GOG-
Ntx Functional Assessment Tool [see appendices 8.4])

Spirometry

Blood Work, urine dipstick pregnancy for women of child bearing potential

Bortezomib/ Placebo SC or IV Administration

Distribute/collect MMF Diary
Visits for Quarterly Assessments and Drug Administration (Visit 7)

Interim H&P(if applicable)

Vital signs

Assess Ae’s and concomitant medications

Spirometry

MRSS and Hopkins Skin Score

QOL assessment and NU PRO

St. George’s and FACIT-dyspnea

6MW

Interim H&P

Toxicity Assessment for Neuropathy (Subjects will complete the 
FACT/GOG-Ntx Functional Assessment Tool [see appendices 8.4])

Blood Work/Serum for Biomarkers, dipstick pregnancy for women of child 
bearing potential

Bortezomib/ Placebo SC or IV Administration
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Visit for Primary Endpoint Evaluation/ Completion of Phase 2 (Visit 10)

Interim H&P (if applicable)

Vital Signs

Assess AE’s and concomitant medications

PFTs

Skin Biopsy (If consented)

MRSS and Hopkins Skin Score

QOL assessment and NU PRO

St. George’s and FACIT-dyspnea

6MW

Toxicity Assessment for Neuropathy (Subjects will complete the 
FACT/GOG-Ntx Functional Assessment Tool [see appendices 8.4])

Blood Work/Serum for Biomarkers
Early Termination Visit (For toxicity, disease progression or patient request)

Interim H&P(if applicable)

Vital signs

Assess AE’s and concomitant medications

PFTs

Skin Biopsy (If consented)

MRSS and Hopkins Skin Score

QOL assessment and NU PRO

St. George’s and FACIT-dyspnea

6MW

Toxicity Assessment for Neuropathy (Subjects will complete the 
FACT/GOG-Ntx Functional Assessment Tool [see appendices 8.4])

Blood Work/Serum for Biomarkers
Follow-up visit (3 months after Primary Endpoint or Early Termination Visit)

Interim H&P(if applicable)
Vital signs
Assess AE'
Spirometry
HRCT (If not done within 3 months of the visit for standard of care)
Skin Biopsy (If consented)
MRSS and Hopkins Skin Score
QOL assessment and NU PRO
St. George’s and FACIT-dyspnea
6MW
Toxicity Assessment for Neuropathy (Subjects will complete the 
FACT/GOG-Ntx Functional Assessment Tool [see appendices 8.4])
Blood Work
3.4.2      STUDY PROCEDURES
Informed Consent
The Investigator will explain the benefits and risks of participation in the study to 
each subject, subject’s legally acceptable representative or impartial witness and 
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obtain written informed consent. Written informed consent must be obtained prior 
to the subject entering the study (before initiation of any study related procedure 
and administration of study drug). The PI will provide the informed consent. The 
final, version dated, form must be agreed to by the PI and the IRB and will contain 
all elements in the sample form, in language readily understood by the subject. 
Each subject’s original consent form, personally signed and dated by the subject or 
by the subject’s legally acceptable representative, and by the physician conducting
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The informed consent discussion, will be retained by the Investigator. The 
Investigator will supply all enrolled subjects or their legally authorized 
representative with a copy of their signed informed consent and assent where 
appropriate The consent form may need to be revised during the trial should 
important new information become available that may be relevant to the safety of 
the subject. In this instance approval should always be given by the IRB and 
existing subjects informed of the changes and re-consented. This is documented in 
the same way as previously described. The Investigator should with the consent of 
the subject or subject’s legally acceptable representative, inform the subject’s 
primary physician about participation in the clinical trial.
Eligibility Criteria
Subjects will be reviewed for eligibility against the inclusion and exclusion criteria.
Medical History
A comprehensive medical history will be undertaken by the investigator to 
determine past and current medical conditions and procedures.
Demographic Information
The following information will be collected: date of birth, height and weight, race, 
gender, age at diagnosis.
Concomitant medications
Medication use that is current will be recorded. In addition all prior therapy and 
duration for SSc will be noted. Generic names are to be used where possible, 
though trade names may be used for combination drugs. Start and stop dates, total 
daily dose, route and indication for use should be recorded. Where possible the 
use of all concomitant medications at the start of the treatment period should be 
maintained throughout the treatment period, and wherever possible, institution of 
new concomitant medications should be avoided.
Physical Examination and Vital Signs
A physical examination must include as a minimum: Vital signs (blood pressure, 
heart rate, respiratory rate, oxygen saturation, and temperature), chest 
auscultation, height and weight. The physical examination should be conducted by 
a physician, but where timing prohibits this, a suitably trained nurse may undertake 
this task. If any doubt exists about the physical status of the subject the physician 
should be consulted.
Pulmonary Function Testing and Spirometry
All study pulmonary function and spirometric testing must be conducted according 
to the ATS/ERS criteria 2005 (64). When possible, pulmonary function testing 
should be performed as close as possible to the same time of the day at each visit. 
All pulmonary function testing should be done in the sitting position, unless the 
subject is obese, who will commonly obtain a deeper inspiration when tested in the 
standing position.
Skin Thickness and Function Scores
Modified Rodnan Skin Score-Clinical assessment of skin thickness will be made in
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each of 17 body areas with 0-3 score with a maximum score of 51. (0=normal, 
1=mild thickness, 2= moderate, 3= severe)
Hopkins Skin Score- Patient reported assessment of skin disease will be evaluated 
based on a 6 component questionnaire using a Likert Scale with a range of 0-10 on 
each component. The score can vary from 0-60.
SKIN BIOPSIES (OPTIONAL)
Two to four total punch biopsies will be performed each time as indicated in the 
protocol. A 3 mm punch will be obtained from the lesional forearm (1x) and from 
non-involved skin like buttocks (x2). 1 piece will be used for RNA (microarrays and 
qPCR-Ancillary Project) and 1 piece will be paraffin embedded for histology and 
immunohistochemistry.
SERUM COLLECTION, PREPARATION AND STORAGE
All blood tests that are obtained for routine clinical care will be recorded in the 
CRF. Subjects will be asked to provide a blood sample for study purposes from an 
existing catheter (i.e. central venous line or arterial catheter) prior to study drug 
initiation and weekly thereafter before and 1 hour after drug administration until 
study drug is stopped. Serum will be aliquotted in 1ml tubes and frozen at -80 C.
HIGH RESOLUTION CHEST CT
Thoracic HRCT will be obtained at the screening visit and at the last 
visit of the study (three-month follow-up visit).  If subjects recently 
completed a chest HRCT scan (within the past three months of each 
visit), the scan may be considered in place of completing another 
scan specifically for the study. The HRCT at screening will be assessed for 
inclusion criteria by Dr. Hart.
SIX-MINUTE WALK TEST
The 6MW walk test will be administered using ATS guidelines (65). The distance 
walked in meters by the patient over 6 minutes will be recorded.
PATIENT REPORTED OUTCOMES
RESPIRATORY SYMPTOM SCORES
St. George’s Respiratory Questionnaire- Symptoms and activity scores are 
calculated using item weights provided in the instrument. The total score is 
calculated from 16 items and their respective weights.
FACIT-Dyspnea- Contains 10 common tasks and respondent is asked to rate 
the severity of dyspnea when performing each task over the previous 7 days. 
They are also asked to rate the difficulty in completing each task due to 
dyspnea. If a task was not completed respondents are asked whether the task 
was not completed due to shortness of breath or because no opportunity to 
perform the task arose.
QUALITY OF LIFE INSTRUMENTS
Short-form-36(SF-36)- The SF-36 is a quality of life questionnaire which yields 
scores for eight domains, as well as two summary scores, a mental component 
summary score (MCS) and a physical component summary score (PCS) (66).
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Promis-29- This Promis-29 is an instrument that contains 7 domains that relate 
to physical, mental and social health and cover most of the relevant areas of 
self-reported health. It includes 4 items in each of the 7 domains as well as 
one11-point rating scale for pain intensity.
Study Drug Administration
The bortezomib and matching placebo will be prepared by the research 
pharmacy at NMH and delivered to the CRU. The CRU staff will be responsible 
for administering the SC injections or IV Infusions (bortezomib or placebo).
3.5
TERMINATION OF TREATMENT AND/OR STUDY PARTICIPATION
Patients will be informed that they have the right to withdraw from the study at any time 
for any reason, without prejudice to their medical care. The investigator also has the 
right to withdraw patients from the study for any of the following reasons:

Occurrence of an unacceptable adverse event

Patient request

Protocol violations

Administrative reasons

Failure to return for follow-up

General or specific changes in the patient’s condition unacceptable for 
further treatment in the judgment of the investigator

Progressive disease at any time

> Persistent 10% drop in FVC from Enrollment Visit

MRSS score increase of 5 or aggressive skin disease progression as 
judged by the investigator
At the time of withdrawal, all study procedures outlined for the End of Study visit should 
be completed. The primary reason for a patient’s withdrawal from the study is to be 
recorded in the source documents. The participant will also be asked to participate in an 
exit visit, either by phone or in person, to document the reason for withdrawal and the 
status of the participant at the time of the withdrawal. Should the participant die, the 
cause of death will be determined and recorded if possible. This additional data will be 
utilized in the statistical analysis of the primary and secondary study outcomes and any 
missing data handled by appropriate statistical methods.
3.6 EFFICACY, PHARMACODYNAMIC/CORRELATIVE 
STUDIES, AND SAFETY MEASUREMENTS
3.6.1Efficacy Measurements
Primary Endpoints

Incidence of serious adverse events (SAE’s)

Annualized change in Forced Vital Capacity
Secondary Endpoints

Change in Modified Rodnan Skin Score

Change in SF-36

Change in St. George’s Respiratory Dyspnea Score

Change in Hopkins Skin Score (Exploratory)

Change in Promis-29 (Exploratory)

Change in FACIT-dyspnea Score (Exploratory)
Exploratory Endpoints

Change in Serum Biomarkers
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
Change in Gene Expression Profile (Skin Biopsies)
3.6.2Pharmacogenomic/Correlative Studies

Change in serum proteasomal activity
3.6.3Safety Measurements
Safety will be assessed by tracking the number and percentage of adverse events at 
48 weeks. In addition subjects will be monitored for changes in a standard panel of 
blood tests. There will interim safety analysis after 8 and 16 patients. Specific 
stopping rules will be in place (See section 5.4.3)
Adverse events
The number and percentage of patients experiencing adverse events will be 
tabulated.
Additional summary data will be presented for:
• Serious adverse events,
• Treatment related adverse events (defined as being possibly, probably or definitely 
related to treatment in the opinion of the investigator),
• Treatment related serious adverse events,
• Adverse events leading to study withdrawal,
• Treatment related adverse events leading to study withdrawal
• Deaths
4.0 ADVERSE EVENTS
4.1 Definitions
4.1.1 Adverse Event Definition
An adverse event (AE) is any untoward medical occurrence in a patient 
administered a pharmaceutical product, which does not necessarily have a 
causal relationship with the treatment. An adverse event can be any 
unfavorable and unintended sign (eg, including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the drug, whether or 
not it is considered to be drug related. This includes any newly occurring event 
or previous condition that has increased in severity or frequency  since the 
administration of drug.
4.1.2 SERIOUS ADVERSE EVENT DEFINITION
A serious adverse event (SAE) is any adverse event, occurring at any dose 
and regardless of causality that:

Results in death.

Is life-threatening. Life-threatening means that the patient was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form.

Requires prolongation of existing hospitalization. Hospitalization 
admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered AEs if the illness 
or disease existed before the patient was enrolled in the trial, provided that it 
did not deteriorate in an unexpected manner during the trial (eg, surgery 
performed earlier than planned).
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
Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a persons’ ability to conduct normal life 
functions.

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.
The causality of SAEs (ie, their relationship to study treatment) will be assessed 
by the investigator(s), who in completing the relevant eCRF must answer “yes” 
or “no” to the question “Do you consider that there is a reasonable possibility 
that the event may have been caused by any of the following – study 
medication? – other medication?”.
Clarification should be made between the terms “serious” and “severe” since 
they ARE NOT synonymous. The term “severe” is often used to describe the 
intensity (severity) of a specific event (as in mild, moderate, or severe 
myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as a severe headache). This is NOT the same as 
“serious,” which is based on patient/event outcome or action criteria described 
above and are usually associated with events that pose a threat to a patient’s 
life or functioning. A severe adverse event does not necessarily need to be 
considered serious. For example, persistent nausea 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.
Note that SAEs that could be associated with any study procedure should also 
be reported. For such events the causal relationship is implied as “yes”.
Other significant adverse events
Significant AEs of particular clinical importance, other than SAEs and those AEs 
leading to discontinuation of the patient from study treatment will be classified as 
OAEs.
4.2PROCEDURES OF AE AND SAE REPORTING
All Investigators and sub-investigators must report all serious adverse events (SAE) 
regardless of relationship with any study drug or expectedness to it’s own IRB and the 
primary investigator-sponsor as soon as possible, but no later than 5 calendar days of 
the investigator’s or sub-investigators observation or awareness of the event. Serious 
adverse events will be captured and reported for 30 days post treatment on the study. 
All sub-investigators must report all SAEs to the investigator-sponsor so that the 
investigator-sponsor can meet his/her foregoing reporting obligations to the IRB at 
Northwestern.
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
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sub-investigator(s). 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.
SAES MUST BE FAXED OR EMAILED TO MILLENNIUM PHARMACOVIGILANCE (OR DESIGNEE):
Toll-Free Fax#: 1-800-963-6290
Email: takedoncocases@cognizant.com
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 4.03, as a guideline, wherever possible. The criteria are 
available online at http://ctep.cancer.gov/reporting/ctc.html.
4.3MONITORING OF ADVERSE EVENTS AND PERIOD OF OBSERVATION
Adverse events, both serious and non-serious, and deaths that occur during the 
patient’s study participation will be recorded in the source documents. All SAEs should 
be monitored until they are resolved or are clearly determined to be due to a patient’s 
stable or chronic condition or intercurrent illness(es).
5.0 STATISTICAL PROCEDURES
5.1 SAMPLE SIZE ESTIMATION
This is a pilot study which will provide data for a sample size estimation for a phase 3 
study.
5.2 POPULATIONS FOR ANALYSIS
Patients who receive at least 1 dose of bortezomib/ placebo will be termed the intention 
to treat (ITT) population. Patients who complete at least 2/3 of the bortezomib/placebo 
doses in the trial will be termed per protocol population (PP) and analyzed separately. 
The main analysis will be performed on the ITT group where measurements will be 
taken at the enrollment and the primary endpoint visit. In an alternative statistical 
analysis we will incorporate as a covariate the actual length of time between ‘first’ and 
‘last’ measurements as it may vary from patient to patient if there is dropout prior to 
completing treatment. The primary and secondary endpoints will be analyzed using the 
ITT and PP populations. Results from the ITT analysis will take precedence over 
findings from the PP analysis. In addition, where possible, pattern mixture models will 
be used to assess the level of ‘randomness’ for missing data.
5.3 PROCEDURES FOR HANDLING MISSING, UNUSED, AND SPURIOUS 
DATA
The primary and secondary endpoints will be analyzed using intention to treat (ITT) and 
PP populations. Results from the ITT analysis will take precedence over findings from 
the PP analysis. Where a subject has missing data on a continuous outcome measure, 
we will use the last measure. The pattern of missing data for the primary endpoint 
variable will be summarized descriptively. In addition, where possible, pattern mixture 
models will be used to assess the level of ‘randomness’ in the missing data patterns.
5.4 STATISTICAL METHODS
5.4.1
BASELINE VARIABLES
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Continuous demographic and clinical variables will be collected in source
documents and displayed as descriptive statistics. Categorical variables 
will be presented in a tabular form.
5.4.2
Efficacy Analysis
Primary efficacy endpoint of annualized FVC decline will compare 
bortezomib and placebo treated cohorts using a t-test.
This is a pilot study in which the primary goal will be to establish safety 
and tolerability of bortezomib or placebo with MMF in SSc-IlD patients. 
Efficacy will be judged by the annualized change in FVC from the 
enrollment visit to the primary endpoint visit of the study. The inclusion 
criteria for the study identifies a cohort that his likely to have a fall in FVC 
of 5% in 1 year if untreated (2). Bortezomib/MMF and Placebo/MMF 
treated cohorts will have annualized change in FVC assessed 
independently. An annualized change in the FVC of 0 will be considered 
pulmonary disease stabilization though we expect FVC improvement 
(See above). Skin scores and QOL measures will also be important 
secondary endpoints and will be assessed similarly to lung function 
changes. Success or failure of secondary endpoints will be based on 
established norms and minimally important clinical differences already 
established for each parameter.
5.4.3
Safety Analysis and stopping rules
Extent of exposure: A summary of exposure to study drug and the duration of 
exposure will be provided.
Adverse events and Serious adverse events: Treatment-emergent adverse events 
(TEAEs) (events which were not present at baseline or worsened in severity 
following the start of treatment) will be presented. Any AEs starting after a 
patient has terminated from the study will not be presented. The following 
summaries will be provided:
• A summary of the number and percentage of patients reporting any 
TEAE, at least one severe TEAE, at least one TEAE possibly related to 
study drug, and at least one TEAE leading to withdrawal from study 
drug.
For each patient and each TEAE, the worst severity recorded will be 
attributed and used in the by-severity summaries.
The following by-patient listing will be provided:
• A listing of all AEs (including non-treatment-emergent events), date of 
onset, date of resolution, duration, severity, seriousness, action taken, 
outcome and relationship to study treatment
Safety will be assessed after the first 8 patients have completed the 
study. The chair of the DSMB will have the option to be unblinded to 
the treatment assignment and the study statistician will compare and 
SAE including mortality in three groups. Safety will be reassessed after 
the next 8 (total of 16) and at the end of study. All serious adverse 
events will be examined by the DSMB. It will be up to the discretion of 
the DSMB to continue or stop the study after each safety analysis.

1st Safety Analysis (after first 8 patients (~25 % of the total) 
have completed the trial): If more than 60% or more patients 
have died or dropped out, the study will be unblinded and if all 
are in the bortezomib group the study will be terminated.

2nd Safety Analysis (after 12 patients (60% of the total) have 
completed the trial): If more than 50% or more patients have
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died or dropped out and more than 80% are in the bortezomib 
group the study will be terminated.
5.5 PROCEDURES FOR REPORTING DEVIATIONS TO ORIGINAL 
STATISTICAL ANALYSIS PLAN

All deviations from the proposed statistical analysis plan will be reported to 
the DSMB
6.1 ADMINISTRATIVE REQUIREMENTS
6.2 Good Clinical Practice
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s). The 
investigator will be thoroughly familiar with the appropriate use of the drug as described in the 
protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. Master files should 
be established at the beginning of the study, maintained for the duration of the study and 
retained according to the appropriate regulations.
6.3 ETHICAL CONSIDERATIONS
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki (see section 8.5). The IRB will review all appropriate study documentation in order to 
safeguard the rights, safety and well-being of the patients. The study will only be conducted at 
sites where IRB approval has been obtained. The protocol, Investigator’s Brochure, informed 
consent, advertisements (if applicable), written information given to the patients (including 
diary cards), safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB by the investigator.
6.4 PATIENT INFORMATION AND INFORMED CONSENT
After the study has been fully explained, written informed consent will be obtained from either 
the patient or his/her guardian or legal representative prior to study participation.  The method 
of obtaining and documenting the informed consent and the contents of the consent will comply 
with ICH-GCP and all applicable regulatory requirement(s).
6.5 PATIENT CONFIDENTIALITY
In order to maintain patient privacy, all data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number. 
The investigator will grant monitor(s) and auditor(s) to the sponsor or his designee and 
regulatory authority(ies) access to the patient’s original medical records for verification of data 
gathered on the data capture records and to audit the data collection process. The patient’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted 
by the applicable laws and regulations.
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6.6 PROTOCOL COMPLIANCE/QUALITY CONTROL
All the study procedures for each visit will be conducted by the nursing staff in the Clinical 
Research Unit (CRU) of Northwestern in collaboration with the research coordinator. The CRU 
staff and the research coordinator will be blinded with respect to randomization. The CRU staff 
and study coordinator will attend an initiation/training session conducted by the PI. This session 
will include a detailed review of the study protocol, study procedures, data collection forms, 
duties of the CRU staff, study coordinator and the procedures for handling blood specimens, 
etc. Quality assurance monitoring for essential study procedures and outcomes will be handled 
by the PI who will prepare independent manuals of operation and monitor quality features of 
every study performed. The PI will meet quarterly with the CRU staff to assure that training, 
staff and instrumentation are in place and being properly used to collect these outcome 
measures. Blinding will be assessed by asking each participant whether they received 
bortezomib or MMF in phase 1 of the trial.
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies). Changes to the protocol will 
require approval from sponsor and written IRB approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
patients. The IRB may provide, if applicable regulatory authority(ies) permit, expedited review 
and approval/favorable opinion for minor change(s) in ongoing studies that have the approval
/favorable opinion of the IRB. The investigator will submit all protocol modifications to sponsor 
and the regulatory authority(ies) in accordance with the governing regulations. Any departures 
from the protocol must be fully documented in the source documents.
6.7 ON-SITE AUDITS
Regulatory authorities, the IRB and/or the sponsor designee 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.
6.8 DRUG ACCOUNTABILITY
Accountability for the drug at all study sites is the responsibility of the principal investigator. 
The investigator will ensure that the drug is used only in accordance with this protocol. Drug 
accountability records indicating the drug’s delivery date to the site (if applicable), inventory at 
the site (if applicable), use by each patient, and return to Millennium or disposal of the drug (if 
applicable and if approved by Millennium) will be maintained by the clinical site. Accountability 
records will include dates, quantities, lot numbers, expiration dates (if applicable), and patient 
numbers. All material containing Bortezomib will be treated and disposed of as hazardous 
waste in accordance with governing regulations.
6.9 PREMATURE CLOSURE OF THE STUDY
This study may be prematurely terminated, if in the opinion of the investigator or sponsor, there 
is sufficient reasonable cause. Written notification documenting the reason for study 
termination will be provided to the investigator or sponsor by the terminating party.
Circumstances that may warrant termination include, but are not limited to:
Determination of unexpected, significant, or unacceptable risk to patients, failure to enter 
patients at an acceptable rate, insufficient adherence to protocol requirements, insufficient 
complete and/or evaluable data, plans to modify, suspend or discontinue the development of 
the drug, should the study be closed prematurely, all study materials must be returned to 
Millennium.
6.10
RECORD RETENTION
The investigator will maintain all study records according to ICH-GC regulatory requirement(s).
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Kaminski, N., Garat, C., Matthay, M. A., Rifkin, D. B., and Sheppard, D. (1999) The integrin alpha 
v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary 
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Formenti, S. C., and Munger, J. S. (2008) Inhibition of integrin alpha(v)beta6, an activator of 
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Q., Liu, X., Rennard, S. I., and Higgins, L. S. (2006) Transforming growth factor-beta receptor 
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Ramirez, A. M., Shen, Z., Ritzenthaler, J. D., and Roman, J. (2006) Myofibroblast 
transdifferentiation in obliterative bronchiolitis: tgf-beta signaling through smad3-dependent 
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Hu, Y., Peng, J., Feng, D., Chu, L., Li, X., Jin, Z., Lin, Z., and Zeng, Q. (2006) Role of extracellular 
signal-regulated kinase, p38 kinase, and activator protein-1 in transforming growth factor-
IRB #: STU00101010 Approved by NU IRB for use on or after 8/14/2020 through 8/13/2021.


45
beta1-induced alpha smooth muscle actin expression in human fetal lung fibroblasts in vitro.
Lung 184, 33-42
31.
Smith, P. C., Caceres, M., and Martinez, J. (2006) Induction of the myofibroblastic phenotype in 
human gingival fibroblasts by transforming growth factor-beta1: role of RhoA-ROCK and c-Jun 
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Transforming growth Factor-beta1 induces phenotypic modulation of human lung fibroblasts to 
myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway. Am J Respir Crit Care 
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Aono, Y., Nishioka, Y., Inayama, M., Ugai, M., Kishi, J., Uehara, H., Izumi, K., and Sone, S. (2005) 
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Daniels, C. E., Wilkes, M. C., Edens, M., Kottom, T. J., Murphy, S. J., Limper, A. H., and Leof, E. B. 
(2004) Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents 
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Ghosh, A. K., Bhattacharyya, S., Lakos, G., Chen, S. J., Mori, Y., and Varga, J. (2004) Disruption of 
transforming growth factor beta signaling and profibrotic responses in normal skin fibroblasts 
by peroxisome proliferator-activated receptor gamma. Arthritis Rheum 50, 1305-1318
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Ghosh, A. K., Wei, J., Wu, M., and Varga, J. (2008) Constitutive Smad signaling and Smad- 
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Milam, J. E., Keshamouni, V. G., Phan, S. H., Hu, B., Gangireddy, S. R., Hogaboam, C. M., 
Standiford, T. J., Thannickal, V. J., and Reddy, R. C. (2008) PPAR-gamma agonists inhibit 
profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. 
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Ciechanover, A., and Iwai, K. (2004) The  ubiquitin system: from basic mechanisms to the 
patient bed. IUBMB Life 56, 193-201
39.
Pan, X., Hussain, F. N., Iqbal, J., Feuerman, M. H., and Hussain, M. M. (2007) Inhibiting 
proteasomal degradation of microsomal triglyceride transfer protein prevents CCl4-induced 
steatosis. J Biol Chem 282, 17078-17089
40.
Anan, A., Baskin-Bey, E. S., Bronk, S. F., Werneburg, N. W., Shah, V. H., and Gores, G. J. (2006) 
Proteasome inhibition induces hepatic stellate cell apoptosis. Hepatology 43, 335-344
41.
Wagner-Ballon, O., Pisani, D. F., Gastinne, T., Tulliez, M., Chaligne, R., Lacout, C., Aurade, F., 
Villeval, J. L., Gonin, P., Vainchenker, W., and Giraudier, S. (2007) Proteasome inhibitor 
bortezomib impairs both myelofibrosis and osteosclerosis induced by high  thrombopoietin 
levels in mice. Blood 110, 345-353
42.
Meiners, S., Hocher, B., Weller, A., Laule, M., Stangl, V., Guenther, C., Godes, M., Mrozikiewicz, 
A., Baumann, G., and Stangl, K. (2004) Downregulation of matrix metalloproteinases and 
collagens and suppression of cardiac fibrosis by inhibition of the proteasome. Hypertension 44, 
471-477
43.
Tashiro, K., Tamada, S., Kuwabara, N., Komiya, T., Takekida, K., Asai, T., Iwao, H., Sugimura, K., 
Matsumura, Y., Takaoka, M., Nakatani, T., and Miura, K. (2003) Attenuation of renal fibrosis by 
proteasome inhibition in rat obstructive nephropathy: possible role of nuclear factor kappaB. 
Int J Mol Med 12, 587-592
44.
Fineschi, S., Reith, W., Guerne, P. A., Dayer, J. M., and Chizzolini, C. (2006)  Proteasome 
blockade exerts an antifibrotic activity by coordinately down-regulating type I collagen and 
tissue inhibitor of metalloproteinase-1 and up-regulating metalloproteinase-1 production in 
human dermal fibroblasts. Faseb J 20, 562-564
IRB #: STU00101010 Approved by NU IRB for use on or after 8/14/2020 through 8/13/2021.


46
45.
Adams, J., Palombella, V. J., Sausville, E. A., Johnson, J., Destree, A., Lazarus, D. D., Maas, J., 
Pien, C. S., Prakash, S., and Elliott, P. J. (1999) Proteasome inhibitors: a novel class of potent 
and effective antitumor agents. Cancer Res 59, 2615-2622
46.
Teicher, B. A., Ara, G., Herbst, R., Palombella, V. J., and Adams, J. (1999) The proteasome 
inhibitor PS-341 in cancer therapy. Clin Cancer Res 5, 2638-2645
47.
Cusack, J. C., Jr., Liu, R., Houston, M., Abendroth, K., Elliott, P. J., Adams, J., and Baldwin, A. S., 
Jr. (2001) Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications 
for systemic nuclear factor-kappaB inhibition. Cancer Res 61, 3535-3540
48.
Hideshima, T., Richardson, P., Chauhan, D., Palombella, V. J., Elliott, P. J., Adams, J., and 
Anderson, K. C. (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and 
overcomes drug resistance in human multiple myeloma cells. Cancer Res 61, 3071-3076
49.
Lightcap, E. S., McCormack, T. A., Pien, C. S., Chau, V., Adams, J., and Elliott, P. J. (2000) 
Proteasome inhibition measurements: clinical application. Clin Chem 46, 673-683
50.
Orlowski, R. Z., Stinchcombe, T. E., Mitchell, B. S., Shea, T. C., Baldwin, A. S., Stahl, S., Adams, J., 
Esseltine, D. L., Elliott, P. J., Pien, C. S., Guerciolini, R., Anderson, J. K., Depcik-Smith, N. D., 
Bhagat, R., Lehman, M. J., Novick, S. C., O'Connor, O. A., and Soignet, S. L. (2002) Phase I trial of 
the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin 
Oncol 20, 4420-4427
51.
Jagannath, S., Barlogie, B., Berenson, J., Siegel, D., Irwin, D., Richardson, P. G., Niesvizky, R., 
Alexanian, R., Limentani, S. A., Alsina, M., Adams, J., Kauffman, M., Esseltine, D. L., Schenkein,
D. P., and Anderson, K. C. (2004) A phase 2 study of two doses of bortezomib in relapsed or 
refractory myeloma. Br J Haematol 127, 165-172
52.
Richardson, P. G., Barlogie, B., Berenson, J., Singhal, S., Jagannath, S., Irwin, D., Rajkumar, S. V., 
Srkalovic, G., Alsina, M., Alexanian, R., Siegel, D., Orlowski, R. Z., Kuter, D., Limentani, S. A., Lee, 
S., Hideshima, T., Esseltine, D. L., Kauffman, M., Adams, J., Schenkein, D. P., and Anderson, K. C. 
(2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348, 2609- 
2617
53.
Richardson, P.  G.,  Sonneveld, P.,  Schuster, M. W.,  Irwin, D., Stadtmauer, E. A.,  Facon, T., 
Harousseau, J. L., Ben-Yehuda, D., Lonial, S., Goldschmidt, H., Reece, D., San-Miguel, J. F., Blade, 
J., Boccadoro, M., Cavenagh, J., Dalton, W. S., Boral, A. L., Esseltine, D. L., Porter, J. B., 
Schenkein, D., and Anderson, K. C. (2005) Bortezomib or high-dose dexamethasone for 
relapsed multiple myeloma. N Engl J Med 352, 2487-2498
54.
Mutlu, G. M., Budinger, G. R., Wu, M., Lam, A. P., Zirk, A., Rivera, S., Urich, D., Chiarella, S. E., 
Go, L. H., Ghosh, A. K., Selman, M., Pardo, A., Varga, J., Kamp, D. W., Chandel, N. S., Sznajder, J. 
I., and Jain, M. (2011) Proteasomal inhibition after injury prevents fibrosis by modulating TGF-
{beta}1 signalling. Thorax
55.
Liu, F. Y., Li, X. Z., Peng, Y. M., Liu, H., and Liu, Y. H. (2007) Arkadia-Smad7-mediated positive 
regulation of TGF-beta signaling in a rat model of tubulointerstitial fibrosis. Am J Nephrol 27, 
176-183
56.
El-Cheikh, J., Michallet, M., Nagler, A., de Lavallade, H., Nicolini, F. E., Shimoni, A., Faucher, C., 
Sobh, M., Revesz, D., Hardan, I., Furst, S., Blaise, D., and Mohty, M. (2008) High response rate 
and improved graft-versus-host disease following bortezomib as salvage therapy after reduced 
intensity conditioning 
allogeneic 
stem cell transplantation 
for multiple myeloma. 
Haematologica 93, 455-458
57.
Mateos-Mazon, J., Perez-Simon, J. A., Lopez, O., Hernandez, E., Etxebarria, J., and San Miguel, J.
F. (2007) Use of bortezomib in the management of chronic graft-versus-host disease among 
multiple myeloma patients relapsing after allogeneic transplantation. Haematologica 92, 1295- 
1296
IRB #: STU00101010 Approved by NU IRB for use on or after 8/14/2020 through 8/13/2021.


47
58.
Miyakoshi, S., Kami, M., Yuji, K., Matsumura, T., Takatoku, M., Sasaki, M., Narimatsu, H., Fujii, 
T., Kawabata, M., Taniguchi, S., Ozawa, K., and Oshimi, K. (2006) Severe pulmonary 
complications in Japanese patients after bortezomib treatment for refractory multiple 
myeloma. Blood 107, 3492-3494
59.
Ogawa, Y., Tobinai, K., Ogura, M., Ando, K., Tsuchiya, T., Kobayashi, Y., Watanabe, T., 
Maruyama, D., Morishima, Y., Kagami, Y., Taji, H., Minami, H., Itoh, K., Nakata, M., and Hotta, T. 
(2008) Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor 
bortezomib in Japanese patients with relapsed or refractory multiple myeloma. Cancer Sci 99, 
140-144
60.
Narimatsu, H., Hori, A., Matsumura, T., Kodama, Y., Takita, M., Kishi, Y., Hamaki, T., Yuji, K., 
Tanaka, Y., Komatsu, T., and Kami, M. (2008) Cooperative relationship between pharmaceutical 
companies, academia, and media explains sharp decrease in frequency of pulmonary 
complications after bortezomib in Japan. J Clin Oncol 26, 5820-5823
61.
Ohri, A., and Arena, F. P. (2006) Severe pulmonary complications in African-American patient 
after bortezomib therapy. Am J Ther 13, 553-555
62.
Boyer, J. E., Batra, R. B., Ascensao, J. L., and Schechter, G. P. (2006) Severe pulmonary 
complication after bortezomib treatment for multiple myeloma. Blood 108, 1113
63.
Palumbo, A., Bringhen, S., Rossi, D., Magarotto, V., Di Raimondo, F., and Ria, R. (2008) A 
Prospective, Randomized , Phase III study of Bortezomib, Melphalan, Prednisone and 
Thalidomide (VMPT) versus Bortezomib, Melphalan, Prednisone in Elderly Newly Diagnosed 
Myeloma Patients. Blood 112, A 652
64.
Pellegrino, R., Viegi, G., Brusasco, V., Crapo, R. O., Burgos, F., Casaburi, R., Coates, A., van der 
Grinten, C. P., Gustafsson, P., Hankinson, J., Jensen, R., Johnson, D. C., MacIntyre, N., McKay, R., 
Miller, M. R., Navajas, D., Pedersen, O. F., and Wanger, J. (2005) Interpretative strategies for 
lung function tests. Eur Respir J 26, 948-968
65.
Laboratories, A. C. o. P. S. f. C. P. F. (2002) ATS statement: guidelines for the six-minute walk 
test. Am J Respir Crit Care Med 166, 111-117
66.
Ware, J. E., Jr., and Gandek, B. (1998) Overview of the SF-36 Health Survey and the 
International Quality of Life Assessment (IQOLA) Project. J Clin Epidemiol 51, 903-912
67.
Tashkin, D. P., Elashoff, R., Clements, P. J., Goldin, J., Roth, M. D., Furst, D. E., Arriola, E., Silver, 
R., Strange, C., Bolster, M., Seibold, J. R., Riley, D. J., Hsu, V. M., Varga, J., Schraufnagel, D. E., 
Theodore, A., Simms, R., Wise, R., Wigley, F., White, B., Steen, V., Read, C., Mayes, M., Parsley, 
E., Mubarak, K., Connolly, M. K., Golden, J., Olman, M., Fessler, B., Rothfield, N., and Metersky,
M. (2006) Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 354, 
2655-2666
IRB #: STU00101010 Approved by NU IRB for use on or after 8/14/2020 through 8/13/2021.


SCREENING
CYCLE 1
CYCLE 2
CYCLE 3
ENROLLMENT VISIT 
1/DAY 1
VISIT 2/DAY 2
VISIT 3/DAY 1
VISIT 4/DAY 2
VISIT 5/DAY1
VISIT 6/DAY 2
INFORMED CONSENT
X
REVIEW MEDICAL HISTORY
X
INTERIM HISTORY
X
X
X
X
X
X
X
DEMOGRAPHICS
X
PHYSICAL EXAM (IF APPLICABLE)
X
X
X
X
X
X
X
PFTS
X
X
6 MINUTE WALK TEST
X
VITAL SIGNS
X
X
X
X
X
X
X
ASSESS AES
X
X
X
X
X
X
X
ASSESS CONCOMITTANT MEDICATIONS
X
X
X
X
X
X
X
SPIROMETRY (PRE-BRONCHODILATOR 
ONLY)
X
X
X
X
X
X
X
RODNAN SKIN SCORE
X
X
St. George’s and FACIT dyspnea
X
HRCT (IF NOT DONE FOR STANDARD OF 
CARE WITHIN 3 MONTHS OF THE VISIT)
X
LABORATORIES(CHEMISTRY/HEMATOLOGY)
X
X
X
X
X
X
X
URINE DIPSTICK PREGNANCY (FEMALES OF 
CHILDBEARING POTENTIAL ONLY)
X
X
X
X
X
X
X
ECG
X
SKIN BIOPSY (OPTIONAL)
X
BLOOD COLLECTION (PROTEASOMAL 
ACT/BIOMARKERS) OPTIONAL
X
QOL ASSESSMENT
X
PATIENT SELF ASSESSMENT
X
HOPKINS SKIN SCORE ASSESSMENT
X
TOLERABILITY AND TOXICITY ASSESSMENT
X
X
X
X
X
X
BORTEZOMIB/PLACEBO ADMINISTRATION
X
X
X
X
X
X


MYCOPHENOLATE (MMF) DIARY 
DISTRIBUTION/COLLECTION
X
X
X
X
X
X
X
CYCLE 4
CYCLE 5
CYCLE 6
PRIMARY 
ENDPOINT/EARLY 
WITHDRAWL
3 MONTH 
FOLLOW 
UP
VISIT 7
VISIT 8
VISIT 9
VISIT 10
VISIT 11
INFORMED CONSENT
REVIEW MEDICAL HISTORY
INTERIM HISTORY
X
X
X
X
X
DEMOGRAPHICS
PHYSICAL EXAM (IF APPLICABLE)
X
X
X
X
X
PFTS
X
X
X
X
X
6 MINUTE WALK TEST
X
X
X
VITAL SIGNS
X
X
X
X
X
ASSESS AES
X
X
X
X
X
ASSESS CONCOMITTANT MEDICATIONS
X
X
X
X
X
SPIROMETRY (PRE-BRONCHODILATOR 
ONLY)
X
X
X
X
X
RODNAN SKIN SCORE
X
X
X
St. George’s and FACIT dyspnea
X
X
X
HRCT (IF NOT DONE FOR STANDARD OF 
CARE WITHIN 3 MONTHS OF THE VISIT)
X
LABORATORIES(CHEMISTRY/HEMATOLOGY)
X
X
X
X
URINE DIPSTICK PREGNANCY (WOMEN OF 
X
X
X


CHILDBEARING POTENTIAL ONLY)
CYCLE 4
CYCLE 5
CYCLE 6
PRIMARY 
ENDPOINT/EARLY 
WITHDRAWL
3 MONTH 
FOLLOW 
UP
VISIT 7
VISIT 8
VISIT 9
VISIT 10
VISIT 11
ECG
X
SKIN BIOPSY (OPTIONAL)
X
X
X
BLOOD COLLECTION (PROTEASOMAL 
ACT/BIOMARKERS) OPTIONAL
X
X
X
QOL ASSESSMENT
X
X
X
PATIENT SELF ASSESSMENT
X
X
X
HOPKINS SKIN SCORE ASSESSMENT
X
X
X
TOLERABILITY AND TOXICITY ASSESSMENT
X
X
X
X
X
BORTEZOMIB/PLACEBO ADMINISTRATION
X
X
X
MYCOPHENOLATE (MMF) DIARY 
DISTRIBUTION/COLLECTION
X
X
X
X
X


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 =
or
BSA =
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as follows: CrCl (ml/min) =  (140-age) (actual wt in kg)
72 x serum creatinine (mg/dl) For females use 85% of calculated CrCl value.
Note: In markedly obese patients, the Cockroft-Gault formula will tend to overestimate the creatinine clearance. (Adipose tissue tends to 
contribute little creatinine requiring renal clearance.)
Ht(inches) Wt(lbs)
3131
Ht(cm) Wt(kg)
3600


54
8.3
Declaration of Helsinki
World Medical Association Declaration of Helsinki:
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by 
the 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General 
Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, 
September 1989 48th WMA General Assembly, Somerset West, Republic of South 
Africa, October 1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, 
October 2000
A. INTRODUCTION
1.
The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical 
research involving human subjects. Medical research involving human subjects includes 
research on identifiable human material or identifiable data.
2.
It is the duty of the physician to promote and safeguard the health of the people. The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty.
3.
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my patient will be my first consideration," and the International Code 
of Medical Ethics declares that, "A physician shall act only in the patient's interest when 
providing medical care which might have the effect of weakening the physical and mental 
condition of the patient."
4.
Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects.
5.
In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society.
6.
The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology 
and pathogenesis of disease.  Even the best proven prophylactic, diagnostic, and 
therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality.
7.
In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens.
8.
Medical research is subject to ethical standards that promote respect for all human beings 
and protect their health and rights. Some research populations are vulnerable and need 
special protection. The particular needs of the economically and medically disadvantaged 
must be recognized. Special attention is also required for those who cannot give or refuse 
consent for themselves, for those who may be subject to giving consent under duress, for 
those who will not benefit personally from the research and for those for whom the research 
is combined with care.
IRB #: STU00101010 Approved by NU IRB for use on or after 8/14/2020 through 8/13/2021.


55
9.
Research Investigators should be aware of the ethical, legal and regulatory requirements 
for research on human subjects in their own countries as well as applicable international 
requirements. No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
1.
It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject.
2.
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation.
3.
Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected.
4.
The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol. This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
investigator, the sponsor or any other kind of undue influence. This independent committee 
should be in conformity with the laws and regulations of the country in which the research 
experiment is performed. The committee has the right to monitor ongoing trials. The 
researcher has the obligation to provide monitoring information to the committee, especially 
any serious adverse events. The researcher should also submit to the committee, for 
review, information regarding  funding, sponsors,  institutional affiliations, other  potential 
conflicts of interest and incentives for subjects.
5.
The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in this 
Declaration.
6.
Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. The 
responsibility for the human subject must always rest with a medically qualified person and 
never rest on the subject of the research, even though the subject has given consent.
7.
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others. This does not preclude the participation of healthy volunteers in 
medical research. The design of all studies should be publicly available.
8.
Physicians should abstain from engaging in research projects involving human subjects 
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.
IRB #: STU00101010 Approved by NU IRB for use on or after 8/14/2020 through 8/13/2021.


56
10. Medical research is only justified if there is a reasonable likelihood that the populations in 
which the research is carried out stand to benefit from the results of the research.
11. The subjects must be volunteers and informed participants in the research project.
12. The right of research subjects to safeguard their integrity must always be respected. Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
patient's information and to minimize the impact of the study on the subject's physical and 
mental integrity and on the personality of the subject.
13. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail. The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without reprisal. 
After ensuring that the subject has understood the information, the physician should then 
obtain the subject's freely-given informed consent, preferably in writing. If the consent 
cannot be obtained in writing, the non-written consent must be formally documented and 
witnessed.
14. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or may 
consent under duress. In that case the informed consent should be obtained by a well- 
informed physician who is not engaged in the investigation and who is completely 
independent of this relationship.
15. For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorized representative in accordance with  applicable  law. 
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons.
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent 
to decisions about participation in research, the investigator must obtain that assent in 
addition to the consent of the legally authorized representative.
17. Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population. The 
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.
IRB #: STU00101010 Approved by NU IRB for use on or after 8/14/2020 through 8/13/2021.


57
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.
IRB #: STU00101010 Approved by NU IRB for use on or after 8/14/2020 through 8/13/2021.


58
8.4 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.
IRB #: STU00101010 Approved by NU IRB for use on or after 8/14/2020 through 8/13/2021.


8.5 New York Heart Association Classification
Class 1-No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea 
(shortness of breath).
Class 2-Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or 
dyspnea.
Class 3-Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, 
or dyspnea.
Class 4-Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical 
activity is undertaken, discomfort is increased.