Clinical trial NCT01891968
Conditions: Leukemia
Keywords: Leukemia Myelodysplastic syndrome MDS Low or intermediate-1 Bortezomib Velcade LDP-341 MLN341 PS-341
Sponsor: M.D. Anderson Cancer Center
Start date: 2013-08-07; Completion date: 2017-01-18
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if bortezomib can help to control MDS. The safety of this drug will also be studied.

Bortezomib is designed to block a protein that causes cells to grow. This may cause cancer cells to die.

Detailed description:
Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive bortezomib as an injection under the skin on Days 1, 4, 8, and 11 of each 21-day cycle.

Study Visits:

At each visit, you will be asked about any drugs you may be taking and any side effects you may be having.

One (1) time a week during Cycle 1, blood (about 2 tablespoons) will be drawn for routine tests.

On Day 21 of Cycles 1 and 3, you will have a bone marrow aspiration and/or biopsy to check the status of the disease and for cytogenetic testing.

On Day 1 of Cycles 2 and beyond, blood (about 2 tablespoons) will be drawn for routine tests.

If your doctor thinks it is needed, you may have additional bone aspirations and/or biopsies to check the status of the disease and/or for cytogenetic testing.

Length of Treatment:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, if you are able to have an allogeneic stem cell transplant (a stem cell transplant from a donor), or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the end-of- treatment visit.

End-of-Treatment Visit:

At 30 days after your last dose of study drug:

* You will be asked about any drugs you may be taking and any side effects you may have had.
* Blood (about 2 tablespoons) will be drawn for routine tests.
* If your doctor thinks it is needed, you will have a bone marrow aspirate and/or biopsy to check the status of the disease and for cytogenetic testing.

This is an investigational study. Bortezomib is FDA approved and commercially available to treat multiple myeloma and mantle cell lymphoma. Giving it to patients with MDS is investigational.

Up to 40 participants will be enrolled in this study. All will take part at MD Anderson.

Arms: arm 1: Bortezomib administered via subcutaneous route at a dose of 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21 day cycle. A course of treatment will be 21 days.
Interventions: intervention 1: Bortezomib
Intervention descriptions: intervention 1: 1.3 mg/m2 subcutaneously on days 1, 4, 8 and 11 of a 21 day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
2012-0562
October 31, 2013
Page 1
Protocol Page
PHASE II STUDY OF SUBCUTANEOUS BORTEZOMIB FOR PATIENTS WITH 
LOW OR INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROME
2012-0562
Core Protocol Information
Short Title 
Bortezomib for low or int-1 MDS with p65 activation
Study Chair: 
Guillermo Garcia-Manero
Additional Contact:
Jhinelle L. Graham
Vicky H. Zoeller
Leukemia Protocol Review Group
Department:
Leukemia
Phone:
713-745-3428
Unit:
428
Full Title: 
PHASE II STUDY OF SUBCUTANEOUS BORTEZOMIB FOR PATIENTS WITH LOW OR 
INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROME
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 01/23/2017
Version:
08
Submitted by:
Vicky H. Zoeller--8/27/2015 10:13:20 AM
OPR Action:
Accepted by:  Debbie D. Stroughter -- 8/28/2015 1:38:37 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


2012-0562
October 31, 2013
Page 2
Protocol Body
 


 
 
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1 
PHASE II STUDY OF SUBCUTANEOUS BORTEZOMIB FOR PATIENTS WITH LOW 
OR INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROME 
 
1.0 
OBJECTIVES 
 
2.0 
BACKGROUND 
 
3.0 
PATIENT SELECTION 
 
4.0 
TREATMENT PLAN 
 
5.0 
DOSING DELAYS/ DOSE MODIFICATIONS 
 
6.0 
AGENT FORMULATION AND PROCUREMENT 
 
7.0 
CORRELATIVE/ SPECIAL STUDIES 
 
8.0 
PATIENT EVALUATION 
 
9.0 
STUDY CALENDAR 
 
10.0 CRITERIA FOR RESPONSE 
 
11.0 CRITERIA FOR REMOVAL FROM THE STUDY 
 
12.0 STATISTICAL CONSIDERATIONS 
 
13.0 PROTOCOL ADMINISTRATION 
 
14.0 REFERENCES 
 
 
 
 
VERSION 2 
 
 
 
 


 
 
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2 
STUDY PRINCIPAL INVESTIGATOR 
 
Guillermo Garcia-Manero, M.D. 
 
 
STUDY CO-INVESTIGATORS 
 
Naval Daver MD (Co-Principal Investigator) 
 
Tapan Kadia MD 
 
Elias Jabbour MD 
 
Zeev Estrov MD 
 
 
Farhad Ravandi M.D. 
 
Hagop Kantarjian M.D. 
 
Carlos Bueso-Ramos M.D. Ph.D. 
 
Lianchun Xiao, Ph.D. 
 
Xuelin Huang, Ph.D. 
 
 
 
 
 
From the Departments of Leukemia, Hematopathology, and Biostatistics,The University 
of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030. 
Telephone:  (713) 792-7026 
 
 
 
 


 
 
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3 
1.0 
OBJECTIVES  
Primary objectives:  
1. To determine the efficacy and clinical activity of subcutaneous (SC) bortezomib in 
patients with low or intermediate-1 myelodysplastic syndrome (MDS) 
Secondary objectives:  
2. To determine the safety and tolerance of SC bortezomib in low or intermediate-1 
MDS 
3. To study the effect of SC bortezomib on modulation of NF-Kb activity in patients with 
low or intermediate-1 MDS by p65 immunohistochemistry staining (ICH) 
 
2.0 
BACKGROUND 
2.1 
MDS 
The myelodysplastic syndromes (MDS) consist of a group of clonal myeloid disorders 
characterized by ineffective hematopoiesis with peripheral blood cytopenias and a 
tendency towards transformation to acute myelogenous leukemia (AML)1,2. The precise 
incidence of MDS is not known, however incidence rates for MDS in the United States 
have been estimated at 1.0 to 12.6 per 100,000 individuals. MDS affects more 
frequently patients of advanced age, particularly those > 60 years of age, that are not 
generally candidates for intensive chemotherapy or bone marrow transplantation 
strategies3. The risk of MDS also appears to be greater in men than in women. MDS is 
a heterogeneous disease. In some patients it manifests as an indolent disease whereas 
in others it is aggressive and may progress rapidly to marrow failure or acute myeloid 
leukemia (AML). MDS can be classified using different systems, such as the French-
American-British (FAB), or the World Health Organization (WHO) classifications4. The 
International Prognostic Score System (IPSS), is a prognostic classification of MDS that 
is widely used to predict survival and progression to AML5. The IPSS combines data on 
the percentage of marrow blasts, cytogenetic alterations and number of cytopenias to 
estimate a patient’s risk category.  With this scoring system, patients are divided into 
low, intermediate (int-1), int-2 and high-risk disease (Table 1). Based on this data, the 


 
 
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4 
median survival of patients with low or int-1 MDS ranges between 3.5 to 5.7 years. For 
the majority of low- or int-1 risk patients (excluding only those with the rare 5q deletion 
or PDGFR gene rearrangement subtypes: approximately 10-15%), specific and highly 
active therapy is not available or approved. Hence, many physicians, especially in the 
community tend to “observe” these patients and do not start specific MDS directed 
therapy. However, patients with low/ int-1 MDS may develop significant cytopenia’s. A 
large number of these patients will become transfusion dependent over time which may 
result in iron overload with its resultant complications including cardiomyopathy, liver 
failure, diabetes and hypothyroidism. Thus, there may be an unmet medical need for 
treatment of low/ int-1 MDS.  
 
Table1. IPSS for MDS  
 
 
Score Value 
 
 
 
Variable 
0 
0.5 
1.0 
1.5 
2.0 
% BM blasts 
5 
5-10 
-- 
11-20 
21-30 
Karyotype 
Good 
Intermediate 
Poor 
 
 
Cytopenias 
0/1 
2/3 
 
 
 
 
Score are as follows: Low: 0; INT-1: 0.5-1.0; INT-2, 1.5-2.0 and high risk  2.5 points. 
Good karyotype includes: diploid, -Y, del(5q), del(20q). Poor karyotype: complex (3 
abnormalities) or chromosome 7 abnormalities. Intermediate karyotype, all others. 
Cytopenias are considered if the absolute neutrophil count is  1800 K/uL; hemoglobin 
less than 10 g/dl and the platelets are less than 105 K/uL. 
 
We have recently completed an analysis of the prognosis of patients with lower risk 
MDS (low and int-1) referred to MDACC over the last 25 years6. We analyzed the 
outcomes of 898 patients previously untreated referred to our center, and have 
developed a prognostic score. The score is based on patient characteristics including 
cytogenetics, age, percentage of blasts, hemoglobin and platelet counts. Based on this 
model, patients with lower-risk MDS can be divided in 3 groups (Figure 1). As can be 
seen in the figure, over 60% of patients with lower risk MDS have poor prognosis. Of 


 
 
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5 
great importance, it should be noted that only 10% of the patients transformed to AML. 
This indicates that a majority of patients with lower risk MDS die as a consequence of 
MDS and not from AML transformation. Therefore the traditional strategy of “watch and 
wait” used by many physicians in patients with lower-risk MDS may not be indicated. 
Therefore new therapies are needed for this subgroup of patients. At the present time, 3 
therapies are approved for patients with MDS in the US. These include 5-azacitidine7, 
lenalidomide8 , and more recently 5-aza-2’-deoxycitidine (decitabine)9. Both 5-
azacitidine and decitabine are hypomethylating agents, whereas lenalidomide is a 
thalidomide derivative. Lenalidomide is indicated for specific subset of patients with 
MDS, in particular those with alterations of chromosome 5 and anemia with low-risk 
disease8. Of importance, most of the clinical benefit with the hypomethylating agents 
has been documented for patients with more advance disease, such as those with int-2 
and high-risk disease7,9,10.  
 
 
 
Figure 1. Survival of patients with lower risk MDS by MDACC score 


 
 
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6 
2.2 
Rationale for the study 
At the present time, 3 pharmacological agents are approved for patients with MDS in 
the United states. These include azacytidine7, 5-aza-2’-deoxycytidine (decitabine)9 and 
lenalidomide8. Most of the clinical benefit from hypomethylating agents (azacytidine and 
decitabine) has been documented in patients with INT-2 or High-risk MDS7,9,11. 
Lenalidomide is only active in a small fraction of patients (those with del5q and anemia, 
approximately 5-10% of patients). Transplant is offered only to a very small group of 
patients with Low/ INT-1 disease. Thus, standard of care in lower risk MDS remains 
suboptimal and there is a need to identify new therapies specifically targeting patients 
with Low/INT-1 MDS.   
Bortezomib is a reversible inhibitor of 26S proteasome and induces apoptosis in human 
cell lines, especially malignant cells of hematopoietic lineage12. Bortezomib induces 
apoptosis by inhibition of the NF-kB pathway13. Leukemic stem cells are highly 
dependent on NF-kB for survival14,15. In-vivo studies have shown that bortezomib can 
inhibit leukemic cell proteasomes resulting in suppression of NF-kB activity in leukemic 
cell lines16,17. Investigators have further shown that MDS progenitors are also highly 
dependent on NF-kB activation for survival18. In clinical studies bortezomib has shown 
modest activity in myeloid neoplasms, both as a single agent and in combination with 
other cytotoxic agents17,19,20.  
We have identified NF-kB activation (p65) in lower risk MDS (Figure 2). We have also 
detected p65 activation in MDS by performing immunohistochemistry on marrow 
specimens of patients with lower risk MDS. In fact P65 activation was noted to be a 
common feature of lower risk MDS. The clinical course of patients with p65 activated 
MDS and their response to therapy remains poorly understood at this time. However, 
we expect that patients with activated p65 will have more advanced disease and 
therefore worse risk. Thus p65 could be a potential target for therapy in MDS. We 
believe that p65 activation serves as a biomarker of NF-kB activation. Hence, we 
hypothesize that subcutaneously administered (SC) bortezomib could have clinical 
activity in patients with lower risk MDS and p65 activation. As mentioned above, in our 
experience, patients with lower risk MDS but poor prognosis merit therapeutic 


 
 
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7 
intervention. We are encouraged by the activity and safety reported with SC bortezomib 
in other clinical condition and therefore the interest in this study. 
 
 
2.3 
Bortezomib (Velcade, PS-341) 
Bortezomib for Injection is a small-molecule proteasome inhibitor developed by 
Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human 
malignancies.  Bortezomib is currently approved by the United States Food and Drug 
Administration (US FDA) for the treatment of patients with multiple myeloma (MM).  It is 
also indicated for the treatment of patients with mantle cell lymphoma (MCL) who have 
received at least 1 prior therapy.  In the European Union (EU), bortezomib in 
combination with melphalan and prednisone is indicated for the treatment of patients 
with previously untreated MM who are not eligible for high-dose chemotherapy with 
bone marrow transplant.  Bortezomib is indicated as monotherapy for the treatment of 
progressive MM in patients who have received at least 1 prior therapy and who have 
already undergone or are unsuitable for bone marrow transplantation. 
By inhibiting a single molecular target, the proteasome, bortezomib affects multiple 
signaling pathways.  The antineoplastic effect of bortezomib likely involves several 
 


 
 
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8 
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.i  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.ii,iii,iv,v,vi,vii,viii,ix,x,xi,xii,xiii,xiv  Notably, bortezomib induces apoptosis in cells that over 
express bcl-2, a genetic trait that confers unregulated growth and resistance to 
conventional chemotherapeutics.xv 
The mechanisms of action leading up to apoptosis have been more clearly defined and 
include initiation of the unfolded protein response and direct/indirect effects on various 
molecular targets including cell cycle control proteins p27 and p21, cyclins, signal 
transduction molecules, transcription factors c-jun and HIF1-,
 tumor suppressor 
protein p53, angiogenesis factors, and many others.  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.xvi,xvii,xviii,xix,xx,xxi,xxii,xxiii 
 
2.4 
Clinical Pharmacokinetics, Pharmacodynamics, Distribution, Metabolism, 
Elimination, Renal impairment: 
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 


 
 
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9 
maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1.0 
mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose. The mean elimination half-life 
of bortezomib upon multiple dosing ranged from 40 to 193 hours. Bortezomib is 
eliminated more rapidly following the first dose. Mean Total Body Clearances were 102 
and 112 L/h following the first dose for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively, 
and ranged from 15 to 32 L/h following subsequent doses for doses of 1.0 and 1.3 
mg/m2, respectively. Clinical experience has shown that the change in clearance does 
not result in overt toxicity from accumulation in this multidose regimen in humans.  
 
In subjects with advanced malignancies, the maximum pharmacodynamic effect 
(inhibition of 20S activity) occurred within 1-hour post dose. At the therapeutic dose of 
1.3 mg/m2 in subjects with multiple myeloma, the mean proteasome inhibition at 1-hour 
post dose was approximately 61%. 
 
The time course of proteasome inhibition in subjects is characterized by maximum 
inhibition observed within the first hour after administration, followed by partial recovery 
of proteasome activity over the next 6 to 24 hours to within 50% of the pretreatment 
activity. On the Day 1, 4, 8, and 11 schedule, variable (10%–30%) levels of proteasome 
inhibition have been observed at next scheduled dosing. In theory, this advantage 
allows cells to recover proteasome activity for normal cellular housekeeping functions 
between doses. 
 
The relationship between bortezomib plasma concentrations and proteasome inhibition 
can be described by a maximum effect (Emax) model. The Emax curve is initially very 
steep, with small changes in plasma bortezomib concentration over the range of 0.5 to 
2.0 ng/mL, relating to large increases in the percent inhibition (0–60%). After that, a 
plateau occurs where marginal increases of proteasome inhibition are observed in spite 
of large changes in plasma bortezomib concentrations. 
 
Subcutaneous administration 


 
 
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Following multiple 1.3 mg/m2 doses, the mean (SD) maximum plasma bortezomib 
concentration (Cmax) was approximately 10 times lower following SC administration 
(20.4 [8.9] ng/mL) compared with IV administration (223 [101] ng/mL), with a short Tmax 
of approximately one-half hour following VELCADE SC injection. However, AUClast was 
equivalent for both routes of administration with a geometric mean ratio (SC to IV) of 
0.992 and 90% CI of 80.18% to 122.80%; ie, within the standard 80 – 125% 
bioequivalence criteria. 
The mean percent inhibition of proteasome activity (Emax) was comparable for the SC 
and IV groups (63.7% vs. 69.3%; respectively) following multiple 1.3 mg/m2 SC or IV 
doses of VELCADE. Mean AUE72 following SC injection was comparable to that of the 
IV injection and within the observed variability (CV = 36 - 55%). 
The exploratory analyses showed that there were no apparent pharmacokinetic or 
pharmacodynamic differences related to the site of SC injection (abdomen versus thigh) 
taking into consideration the small sample size of the 
pharmacokinetic/pharmacodynamic part of the study. 
Bortezomib was reconstituted to a concentration of 2.5 mg/mL for SC administration. In 
the randomized Phase 1 study CAN-1004, bortezomib was injected subcutaneously in a 
concentration of 1 mg/mL. The pharmacokinetic and pharmacodynamic parameters of 
the SC administration were comparable between the 2 studies (Table 1). Thus, the 
concentration of the SC injected solution does not appear to influence bortezomib 
pharmacokinetics or pharmacodynamics. The pharmacokinetic and pharmacodynamic 
parameters following IV administration in the current study were also comparable to 
those observed previously for IV administrationxxiv. 


 
 
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Table 1:  Summary of Pharmacokinetic and Pharmacodynamic Parameters  
Following Subcutaneous Injections of VELCADE 1.3 mg/m2 Using 2.5 mg/mL and 
1.0 mg/mL Solutions 
Parameter 
2.5 mg/mLa 
1.0 mg/mLb 
Cmax (ng/mL)c 
20.4 (8.87) 
22.5 (5.36) 
Tmax (h)d 
0.5 (0.08-1.00) 
0.5 (0.25-1.00) 
AUClast (ng.h/mL)c 
155 (56.8) 
195 (51.2) 
AUE72 (%.h)c 
1714 (617) 
1619 (804) 
Emax (%)c 
63.7 (10.6) 
57.0 (12.8) 
AUClast=area under the plasma concentration-time curve from time 0 to the time of 
last quantifiable time point; AUE72=area under the percent inhibition-time curve from 
time 0 to 72 hours; Emax=observed maximum percent inhibition of 20S proteasome 
activity (ChT:T); h=hours; SD=standard deviation; Tmax=time when Cmax is observed 
a 26866138-MMY-3021 
b 26866138-CAN-1004 
c Mean (SD) 
d Median (range)  
 
The mean distribution volume of bortezomib ranged from approximately 498 to 1884 
L/m2 following single- or repeat-dose administration of 1 mg/m2 or 1.3mg/m2 to patients 
with multiple myeloma. This suggests bortezomib distributes widely to peripheral 
tissues. The binding of bortezomib to human plasma proteins averaged 83% over the 
concentration range of 100 to 1000 ng/mL. 
 
In vitro studies with human liver microsomes and human cDNA-expressed cytochrome 
P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via 
cytochrome P450 enzymes 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 
and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 
deboronated metabolites that subsequently undergo hydroxylation to several 
metabolites. Deboronated bortezomib metabolites are inactive as 26S proteasome 
inhibitors. Pooled plasma data from 8 patients at 10 min and 30 min after dosing 
indicate that the plasma levels of metabolites are low compared to the parent drug.  


 
 
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The pathways of elimination of bortezomib have not been characterized in humans.A 
pharmacokinetic study was conducted in patients with various degrees of renal 
impairment who were classified according to their creatinine clearance values (CrCl) 
into the following groups: Normal (CrCl _60 mL/min/1.73 m2, N=12), Mild (CrCl=40-59 
mL/min/1.73 m2, N=10), Moderate (CrCl=20-39 mL/min/1.73 m2, N=9), and Severe 
(CrCl < 20 mL/min/1.73 m2, N=3). A group of dialysis patients who were dosed after 
dialysis was also included in the study (N=8). Patients were administered intravenous 
doses of 0.7 to 1.3 mg/m2 of bortezomib twice weekly. Exposure of bortezomib (dose 
normalized AUC and Cmax) was comparable among all the groups. 
 
Clinical Experience 
It is estimated that as of June 2011, more than 300,000 patients have been treated with 
bortezomib, including patients treated through Millennium-sponsored clinical trials, 
Investigator-Initiated Studies, the US NCI Cancer Therapy Evaluation Program (CTEP), 
and with commercially available drug.  Bortezomib has been commercially available 
since 13 May 2003. 
The overall goal of the Millennium phase 1 program was to determine the MTD and 
dose-limiting toxicity (DLT) of bortezomib in a number of therapeutic settings involving 
subjects with various advanced malignancies.  In a phase 1 trial in patients with 
refractory hematologic malignancies, the MTD for a twice weekly dosing for 4 weeks of 
a 42-day cycle was 1.04 mg/m2/dose, with DLTs of thrombocytopenia, hyponatremia, 
hypokalemia, fatigue, and malaise.xxv  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. 


 
 
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In phase 1 clinical studies, antitumor activity was reported in subjects with Non-
Hodgkin’s Lymphoma (NHL), MM, Waldenström’s Macroglobulinemia, squamous cell 
carcinoma of the nasopharynx, bronchoalveolar carcinoma of the lung, renal cell 
carcinoma, and prostate cancer.xxvi,xxvii,xxviii,xxix 
The safety and efficacy of bortezomib in subjects with MM were investigated in two 
phase 2 clinical studies, studies M34100-024 (subjects with first relapse)xxx and 
M34100-025 (subjects with second or greater relapse and refractory to their last prior 
therapy).xxxi  In M34100-025, 202 heavily pretreated subjects with refractory MM after at 
least 2 previous treatments received bortezomib, 1.3 mg/m2 on Days 1, 4, 8, and 11 of a 
21-day treatment cycle.  The European Group for Blood and Marrow Transplant (EBMT) 
response criteria, as described by Bladexxxii were utilized to determine disease 
response.  Complete responses (CRs) were observed in 4% of subjects, with an 
additional 6% of patients meeting all criteria for CR but having a positive immunofixation 
test.  Partial response (PR) or better was observed in 27% of subjects, and the overall 
response rate (CR, PR, and minor response [MR] combined) was 35%.  Seventy 
percent of subjects experienced stable disease or better. 
The phase 3 study (M34101-039)xxxiii, also referred to as the APEX study, was designed 
to determine whether bortezomib provided benefit (time to progression [TTP], response 
rate, and survival) to patients with relapsed or refractory MM relative to treatment with 
high-dose dexamethasone.  The study was also designed to determine the safety and 
tolerability of bortezomib relative to high-dose dexamethasone, and whether treatment 
with bortezomib was associated with superior clinical benefit and quality of life relative 
to high-dose dexamethasone.  A total of 669 patients were enrolled and 663 patients 
received study drug (bortezomib:  331; dexamethasone:  332).  Patients randomized to 
bortezomib received 1.3 mg/m2 IV push twice weekly on Days 1, 4, 8, and 11 of a 3-
week cycle for up to 8 treatment cycles as induction therapy, followed by 1.3-mg/m2 
bortezomib weekly on Days 1, 8, 15, and 22 of a 5-week cycle for 3 cycles as 
maintenance therapy.  Patients randomized to dexamethasone received oral 
dexamethasone 40 mg once daily on Days 1 to 4, 9 to 12, and 17 to 20 of a 5-week 
cycle for up to 4 treatment cycles as induction therapy, followed by dexamethasone 40 
mg once daily on Days 1 to 4 of a 4-week cycle for 5 cycles as maintenance therapy.  


 
 
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The EBMT response criteria were utilized to determine disease response.  There was a 
78% increase in TTP for the bortezomib arm.  Median TTP was 6.2 months for the 
bortezomib arm and 3.5 months for the dexamethasone arm (p < 0.0001).  CR + PR 
was 38% with bortezomib versus 18% with dexamethasone (p  0.0001).  CR was 6% 
with bortezomib versus  1% with dexamethasone (p < 0.0001).  The CR + nCR (near 
CR) rate was 13% with bortezomib versus 2% with dexamethasone.  In patients who 
had received only 1 prior line of treatment (bortezomib:  132; dexamethasone:  119), CR 
+ PR was 45% with bortezomib vs 26% with dexamethasone (p = 0.0035).  With a 
median 8.3 months of follow-up, overall survival was significantly longer (p = 0.0013) for 
patients on the bortezomib arm versus patients on the dexamethasone arm.  The 
probability of survival at 1 year was 80% for the bortezomib arm versus 66% for the 
dexamethasone arm, which represented a 41% decreased relative risk of death in the 
first year with bortezomib (p = 0.0005).  In patients who had received only 1 prior line of 
treatment, the probability of survival at 1 year was 89% for the bortezomib arm versus 
72% for the dexamethasone arm, which represented a 61% decreased relative risk of 
death in the first year with bortezomib (p = 0.0098).  Updated response rates and 
survival data were reported for M34101-039.xxxiv  The updated CR + PR rate was 43% 
with bortezomib.  The CR + nCR rate was 16% with bortezomib.  With a median 
22 months of follow-up, overall survival was significantly longer for patients on the 
bortezomib arm versus patients on the dexamethasone arm.  The median overall 
survival was 29.8 months (95% CI:  23.2, not estimable) for the bortezomib arm vs 23.7 
months (95% CI:  18.7, 29.1) for the dexamethasone arm (hazard ratio = 0.77, 
p = 0.0272).  The probability of survival at 1 year was 80% for the bortezomib arm 
versus 67% for the dexamethasone arm (p = 0.0002). 
The safety and efficacy of bortezomib in relapsed or refractory mantle cell lymphoma 
(MCL) were investigated in an international, phase 2, multicenter study M34103-053, 
also referred to as the PINNACLE study.xxxv  The single-arm study was designed to 
evaluate the response rates, duration of response (DOR), TTP, overall survival (OS), 
and safety of bortezomib treatment in patients with relapsed or refractory mantle cell 
lymphoma.  For 141 evaluable patients, the response rate was 31% (8% 
CR/unconfirmed CR [Cru]).  Median time to response was 40 days (range 31-204 days).  


 
 
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15
The median number of cycles administered across all patients was 4; in responding 
patients, the median number of cycles was 8.  The median DOR by algorithm was 9.2 
months and 13.5 months in patients with CR/CRu.  Median TTP for both groups was 6.2 
months.  With a median follow-up of 13.4 months, overall survival had not been 
reached.  The most commonly reported adverse events (AEs) were fatigue, peripheral 
neuropathy, and gastrointestinal events.  A time-to-event update to the PINNACLE 
studyxxxvi was reported after a median follow-up of 26.4 months.  TTP was 6.7 months 
for all patients, 12.4 months in all responders.  The median DOR was 9.2 months in all 
responders and had not been reached in patients achieving CR/Cru.  Overall survival 
was 23.5 months in all patients and 36 months in patients with CR/Cru.  Survival at 12 
months was 69% overall and 91% in responding patients. 
The phase 3 study (MMY 3002) known as the VISTA study, evaluated the safety and 
efficacy of the combination of bortezomib, melphalan, and prednisone in previously 
untreated multiple myeloma patients who were not candidates for stem cell 
transplant.xxxvii  The study was designed to determine the benefit of adding bortezomib 
to MP (melphalan and prednisone) as assessed by TTP.  Patients (682) were 
randomized to receive nine 6-week cycles of melphalan 9mg/m2 and prednisone 
60 mg/m2 on Days 1 to 4, alone or in combination with bortezomib 1.3 mg/m2 by IV 
bolus on Days 1, 4, 8, 11, 22, 25, 29, and 32 during Cycles 1 to 4, and on Days 1, 8, 22, 
and 29 during Cycles 5 to 9.  Response was evaluated every 3 weeks using the EBMT 
criteria.  At a preplanned interim analysis, the independent data monitoring committee 
recommended that the study be stopped since the prespecified statistical boundary end 
point of TTP had been crossed.  Response rates were 30% with 4% CR.  The rates of 
partial response or better were 71% in the bortezomib (VMP) group compared to 34% in 
the MP group (p = 0.001).  With follow-up of 16.3 months, the TTP for the VMP group 
was 24 months compared to 16.6 months in the MP group (p = 0.000001) and was 
associated with a 52% reduced time to progression.  The median DOR was 19.9 
months in the VMP group and 13.1 months in the MP group.  Overall survival had not 
been reached in either group.  Hematologic toxicity was similar in both groups.  The 
incidence of peripheral sensory neuropathy and gastrointestinal symptoms was higher 
in the VMP group.  The incidence of herpes zoster was 3% in patients in the VMP group 


 
 
Protocol 2012-0562 
 
 
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16
who received antiviral prophylaxis.  Fifteen percent of patients in the VMP group 
discontinued therapy due to AEs compared to 14% in the MP group. 
The VISTA study update after extended follow-up of 25.9 months,xxxviii confirmed a 
survival benefit for the VMP group.  Overall survival was not reached in either group:  
VMP group (75) deaths, 3 year OS 72%; MP group (111) deaths, 3 year OS 59% 
(p = 0.0032).  Patients on VMP were less likely to start second-line therapy (VMP 38% 
vs MP 57% at the time of data cut-off) with a longer time to next therapy (TNT) and 
treatment free interval (TFI).  Of the MP patients who received subsequent therapy, 
43% went on to receive bortezomib. 
Based on investigator-reported best responses to subsequent therapies, patients 
relapsing after therapy with a novel agent were not intrinsically more resistant than after 
receiving a traditional agent. 
In the VISTA study, VMP was associated with prolonged TTP, TNT, TFI, and OS.  
Patients were successfully treated with subsequent IMiD-based therapy and retreated 
with bortezomib.  After 36.7 months follow-up, OS continued to be superior for 
VMP.  The OS for VMP had not yet been reached compared to MP (43.1 months).xxxix In 
an updated analysis of overall survival based on 387 deaths (median follow-up 60.1 
months), the median overall survival for VMP was 56.4 months and the MP was 43.1 
months, with a hazard ration of 0.695 (95% CI: 0.57, 0.85).43 
SUBCUTANEOUS ADMINISTRATION  
A randomized Phase 1 pilot study in 24 subjects with multiple myeloma demonstrated 
that both the IV and SC routes of bortezomib administration have similar systemic drug 
exposure and proteasome inhibition. Importantly, SC and IV administration of 
bortezomib appeared to result in similar efficacy profiles (ie, response rate) and similar 
safety profiles. The pilot study also provided preliminary evidence of good local 
tolerance for SC injection of bortezomib, when administered at 1 mg/mL concentrationxl.  
The data from the Phase 1 pilot study formed the basis of the design of a randomized, 
Phase 3 study that compared the efficacy and safety of subcutaneous versus 
intravenous bortezomib at the approved 1.3 mg/m(2) dose and twice per week schedule 


 
 
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17
in patients with relapsed multiple myelomaxxiv. 222 patients were randomly assigned in a 
2:1 ratio to receive either subcutaneous (n=148) or intravenous (n=74) bortezomib. The 
response-evaluable population consisted of 145 patients in the subcutaneous group and 
73 in the intravenous group. Patients received a median of eight cycles (range one to 
ten) in both groups.  
The ORR (CR+PR) after 4 cycles of treatment, assessed by computer algorithm 
implementation of EBMT response criteria, was 42 % in both the SC and IV treatment 
groups for the response-evaluable population. The ORR after 4 cycles in the IV arm 
was consistent with what was observed in historical single-agent bortezomib trials with 
relapsed multiple myeloma subjects. The stratified Mantel-Haenszel estimate of the 
relative risk of achieving response for SC treatment group versus IV treatment group 
was 0.99 with 95% CI (0.71, 1.37). The 95% CI for ORR_SC - 0.6 ORR_IV was (6.1, 
27.1), which excludes 0. Thus the study met the noninferiority objective (p-value for the 
noninferiority hypothesis was 0.00201). Results in the ITT population were similar; 
noninferiority of SC versus IV was also demonstrated. 
The CR rate after 4 cycles of treatment was 6% in the SC treatment group and 8% in 
the IV treatment group; the nCR rate after 4 cycles of treatment was 6% in the SC 
treatment group and 5% in the IV treatment group; the VGPR rate after 4 cycles of 
treatment was 4% in the SC treatment group and 3% in the IV treatment group. 
Therefore, 17% subjects in the SC treatment group and 16% subjects in the IV 
treatment group had obtained at least VGPR after the first 4 cycles. 
The ORR (CR+PR) after 8 cycles of treatment was 52% in both the SC and IV treatment 
groups for the response-evaluable population. The stratified Mantel-Haenszel estimate 
of the common relative risk of achieving response for SC versus IV was 1.00 with 95% 
CI (0.77, 1.31). Twenty-five percent of subjects in the SC treatment group and 25% of 
subjects in the IV treatment group had obtained at least VGPR during the first 8 cycles. 
The median TTP (Kaplan-Meier estimate) was 10.4 months in the SC treatment group 
and 9.4 months in the IV treatment group. The hazard ratio was 0.839 with 95% CI 
(0.564, 1.249), and the p=0.3866 (stratified log-rank test), indicating similar results 
between the SC and IV arm. 


 
 
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18
The median PFS (Kaplan-Meier estimate) was 10.2 months in the SC treatment group 
and 8.0 months in the IV treatment group. The hazard ratio was 0.824 with 95% CI 
(0.574, 1.183), and the p=0.2945 (stratified log-rank test), indicating comparable results 
between the SC and IV arm.  
After a median follow-up of 11.8 months, the 1-year survival rate was 72.6% in the SC 
arm and 76.7% in the IV arm. The p-value for the difference in 1-year survival rate was 
0.5037, indicating similar results between the SC and IV arm. 
The median time to first response (Kaplan-Meier estimate) was 3.5 months for both the 
SC and IV treatment groups. The hazard ratio was 1.059 with 95% CI (0.716, 1. 567), 
and the p=0.7725 (stratified log-rank test), indicating similar results between the SC and 
IV arm. Among the responders, the median time to first response was 1.4 months 
(44 days) in the SC arm and 1.4 months (43 days) in the IV arm. Among the 
responders, the median duration of response (Kaplan-Meier estimate) was 9.7 months 
in the SC treatment group, compared with 8.7 months in the IV treatment group. 
Overall, similar efficacy results were observed in the SC and IV treatment groups, and 
the study demonstrated that bortezomib SC administration is not inferior to bortezomib 
IV administrationxxiv. 
2.5 
Source, Preparation, Handling, Storage, Stability, Administration: 
Bortezomib, manufactured under an IND in the same conditions as commercial 
Velcade™, will be provided by Millennium Pharmaceuticals, Inc. Bortezomib (VELCADE 
for Injection) is a sterile lyophilized powder for reconstitution and is supplied in vials 
containing 3.5 mg of bortezomib and 35 mg of mannitol. Unopened vials may be stored 
at controlled room temperature 25º C (77º F); excursions permitted from 15º to 30º C 
(59º to 86º F). 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. Retain in original 
package to protect from light.  
 


 
 
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19
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. 
 
Prior to use, the contents of each vial must be reconstituted with 3.5 mL of normal 
(0.9%) saline (sodium chloride injection). The reconstituted product should be a clear 
and colorless solution. Bortezomib contains no antimicrobial preservative. When 
reconstituted as directed, bortezomib may be stored at 25°C (77°F). The reconstituted 
material may be stored in the original vial and/or the syringe prior to administration. The 
product may be stored for up to 8 hours in a syringe; however, total storage time for the 
reconstituted material must not exceed 8 hours when exposed to normal indoor lighting 
 
2.6 
Bortezomib Destruction 
For commercially-labeled VELCADE for IND-exempt studies, please contact your 
Millennium Clinical Operations representative to arrange for return of study drug 
procedures.  Any unused or expired VELCADE must be returned to Millennium.  Be 
sure to document drug return on your drug accountability logs. 
 
2.7 
Potential Risks  
To date, more than 300,000 patients have been treated with bortezomib in both clinical 
 trials investigating its use in hematological malignancies and solid tumors, and in 
patients who were treated with commercially available bortezomib.  Prescribing 
physicians and health care practitioners are referred to their locally approved product 
label for bortezomib regarding Indications and Usage, Contraindications, Warnings, and 
Precautions.The known anticipated risks of bortezomib therapy are presented in Table 
0-1 and Table 0-2.  These risks are grouped according to the combined frequency 
observed in an integrated analysis of AEs in sponsored clinical studies of single-agent 


 
 
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20
bortezomib dosed at 1.3 mg/m2 twice weekly on a 21-day schedule, in patients with 
multiple myeloma and mantle cell lymphoma. 
Table 0-1    Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Blood and Lymphatic System Disorders 
Most common 
Thrombocytopenia*, anaemia* 
Very common  
Neutropenia* 
Common  
Lymphopenia, pancytopenia*, leukopenia*, 
febrile neutropenia 
Cardiac Disorders 
Common  
Tachycardia, atrial fibrillation, palpitations, 
cardiac failure congestive* 
Uncommon 
Cardiogenic shock*, atrial flutter, cardiac 
tamponade*, bradycardia, atrioventricular 
block complete, arrhythmia, cardiac arrest, 
cardiac failure, arrhythmia, pericardial effusion, 
pericarditis, pericardial disease, 
cardiopulmonary failure 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impaired 
Eye Disorders 
Common  
Blurred vision, conjunctivitis, conjunctival 
haemorrhage  
Gastrointestinal Disorders 
Most common 
Constipation, diarrhoea*, nausea, vomiting* 
Very common  
abdominal pain (excluding oral and throat) 
Common  
Dyspepsia, pharyngolaryngeal pain, 
gastroesophageal reflux, abdominal distension, 
gastritis, stomatitis, mouth ulceration, 
dysphagia, gastrointestinal haemorrhage*, 
lower gastrointestinal haemorrhage*± rectal 
haemorrhage 
Uncommon 
Eructation, gastrointestinal pain, tongue 
ulceration, retching, upper gastrointestinal 
haemorrhage*, haematemesis*, oral mucosal 
petechiae, ileus paralytic*, ileus, odynophagia, 
enteritis, colitis, oesophagitis, enterocolitis, 
diarrhoea haemorrhagic, acute pancreatitis*, 
intestinal obstruction 


 
 
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21
Table 0-1    Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
General Disorders and Administration Site Conditions 
Most common 
Fatigue, pyrexia 
Very common  
Chills, oedema peripheral, asthenia 
Common  
Neuralgia, lethargy, malaise, chest pain, 
mucosal inflammation* 
Uncommon 
Injection site pain, injection site irritation, 
injection site phlebitis, general physical health 
deterioration*, catheter-related complication 
Hepatobiliary Disorders 
Uncommon 
Hyperbilirubinaemia, hepatitis* 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 
Infections and Infestations 
Very common  
Upper respiratory tract infection, 
nasopharyngitis, pneumonia*, Herpes zoster* 
Common  
Lower respiratory tract infection*, sinusitis, 
pharyngitis, oral candidiasis, urinary tract 
infection*, sepsis, bactaeremia*, cellulitis, 
Herpes simplex, bronchitis, gastroenteritis*, 
infection 
Uncommon 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung 
infection, infusion site cellulitis, catheter site 
cellulitis, infusion site infection, urosepsis*, 
Aspergillosis*, tinea infection, Herpes zoster 
ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic, varicella, 
empyema, fungal oesophagitis 
Injury, Poisoning, and Procedural Complications  
Common 
Fall 
Uncommon 
Subdural haematoma 
Investigations 
Common  
Weight decreased, alanine aminotransferase 
(ALT) increased, aspartate aminotransferase 
(AST) increased, blood alkaline phosphatase 
increased, liver function test abnormal, blood 
creatinine increased* 


 
 
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22
Table 0-1    Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Uncommon 
Gamma-glutamyltransferase (GGT) increased, 
oxygen saturation decreased*, blood albumin 
decreased, ejection fraction decreased* 
Metabolism and Nutritional Disorders 
Very common  
Decreased appetite, anorexia, dehydration* 
Common  
Hyperglycaemia, hypoglycaemia, 
hyponatraemia, hypokalaemia, 
hypercalcaemia* 
Musculoskeletal and Connective Tissue Disorders 
Very common  
Bone pain, myalgia, arthralgia, back pain 
Common 
Muscular weakness 
Uncommon 
Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and polyps) 
Uncommon 
Tumour lysis syndrome* 
Nervous System Disorders 
Most common 
Peripheral neuropathy (including all preferred 
terms under the MedDRA High-level term 
Peripheral neuropathy NEC) 
Very common  
Paresthesia, dizziness excluding vertigo, 
headache 
Common  
Polyneuropathy, syncope, dysesthesia, 
dysgeusia, postherpetic neuralgia 
Uncommon 
Convulsion, loss of consciousness, ageusia, 
encephalopathy, paralysis*,autonomic 
neuropathy, reversible posterior 
leukoencephalopathy syndrome, posterior 
reversible encephalopathy syndrome  
Psychiatric Disorders 
Very common 
Anxiety, insomnia  
Common 
Confusional state  
Uncommon 
Delirium 
Renal and Urinary Disorders 
Common 
Renal impairment*, renal failure*, haematuria 
Uncommon 
Micturition disorder 
Respiratory, Thoracic, and Mediastinal Disorders 
Very common 
Cough, dyspnoea  


 
 
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23
Table 0-1    Known Anticipated Risks of Bortezomib by MedDRA System Organ 
Class, Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
Common 
Epistaxis, dyspnoea exertional, pleural 
effusion*, rhinorrhea, hypoxia*, pulmonary 
oedema 
Uncommon 
Hemoptysis*, acute respiratory distress 
syndrome*, respiratory failure*, pneumonitis*, 
lung infiltration, pulmonary alveolar 
haemorrhage*, interstitial lung disease*, 
pulmonary hypertension*, pleurisy, pleuritic 
pain 
Skin and Subcutaneous Tissue Disorders 
Very common 
Rash 
Common 
Rash pruritic, rash erythematous, urticaria, 
petechiae 
Uncommon 
Cutaneous vasculitis, leukocytoclastic 
vasculitis  
Vascular Disorders 
Common 
Hypotension*, orthostatic hypotension 
Uncommon 
Cerebral haemorrhage* 
Source:  VELCADE® (bortezomib) for Injection Investigator’s Brochure Edition 15. 
Most common =  30%, Very common = 10% to 29%, Common = 1% to 9%, 
Uncommon = < 1%. 
* Fatal outcomes have been reported. 
 Indicates a Preferred term not listed in the source table, however the event is 
deemed medically important and so is included. 
Effective MedDRA update to version 14.0, the term ‘reversible posterior 
leukoencephalopathy syndrome’ updated to ‘posterior reversible encephalopathy 
syndrome (PRES)’. 
 
Table 0-2    Reports of Adverse Reactions From Postmarketing Experience 
System Organ Class 
 
Preferred Term 
Observed 
Incidencea 
Blood and lymphatic system disorders 
 
 
Disseminated intravascular coagulation  
Rare 
Cardiac Disorders 
 
 
Atrioventricular block complete 
Rare 


 
 
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24
Table 0-2    Reports of Adverse Reactions From Postmarketing Experience 
System Organ Class 
 
Preferred Term 
Observed 
Incidencea 
 
Cardiac tamponade 
Rare 
Ear and labyrinth disorders 
 
 
Deafness bilateral 
Rare 
Eye Disorders 
 
 
Ophthalmic herpes 
Rare 
              Optic neuropathy 
Rare 
              Blindness 
Rare  
Gastrointestinal Disorders 
 
 
Acute pancreatitis  
Rare 
 
Ischemic colitis 
Rare 
Hepatobiliary disorders 
 
 
Hepatitis 
Uncommon 
 
Liver failure 
Unknown 
Infections and infestations 
 
 
Herpes meningoencephalitis 
Rare 
 
Septic shock 
Rare 
Progressive multifocal leukoencephalopathy 
Very rare 
Immune System Disorders 
 
 
Angioedema 
Rare 
Nervous System Disorders 
 
 
Autonomic neuropathy 
Rare 
 
Dysautonomia 
Unknown 
 
Encephalopathy 
Rare 
Respiratory, thoracic and mediastinal disorders: 
 
 
Acute diffuse infiltrative pulmonary diseaseb  
Rare 
 
Acute respiratory distress syndrome (ARDS) 
Rare 
 
Interstitial pneumonia 
Rare 
 
Lung infiltration 
Rare 
 
Pneumonitis 
Rare 
 
Pulmonary hypertension 
Rare 


 
 
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25
Table 0-2    Reports of Adverse Reactions From Postmarketing Experience 
System Organ Class 
 
Preferred Term 
Observed 
Incidencea 
Skin and subcutaneous system disorders 
 
 
Acute febrile neutrophilic dermatosis 
Unknown 
 
Toxic epidermal necrolysis 
Unknown 
Source:  VELCADE® (bortezomib) for Injection Investigator’s Brochure Edition 15 
Addendum 1. 
a Incidence is assigned using the following convention:  very common ( 1/10); 
common ( 1/100 and  1/10); uncommon ( 1/1000 and  1/100); rare 
( 1/10,000 and  1/1000 ); very rare ( 1/10,000, including isolated reports). 
b Acute diffuse infiltrative pulmonary disease is a MedDRA Lower Level Term 
which corresponds to a Preferred Term of Interstitial lung disease. 
 
Other medical events of interest that are considered not causally related to 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. 
Additional details on the potential risks of bortezomib may be found in the current 
Investigator’s Brochure.  
 
SAFETY SUMMARY FOR SUBCUTANEOUS ADMINISTRATION   
While the safety profile between the SC and IV treatment groups in general was 
comparable in most System Organ Classes (SOCs), a difference in incidence in certain 
safety parameters in favor of the SC treatment group was noted. One hundred and forty 
(95%) subjects in the SC treatment group and 73 (99%) subjects in the IV treatment 
group reported at least 1 treatment-emergent adverse event. In the SC treatment group, 
there was a lower incidence of Grade 3 adverse events as compared with the IV 
treatment group (57% vs. 70%, respectively); a lower incidence of adverse events 
leading to treatment discontinuations (22% in the SC treatment group and 27% in the IV 
treatment group); and a lower incidence of adverse events leading to dose modifications 


 
 
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26
in the SC group: dose reduction (33% in the SC treatment group compared with 45% in 
the IV treatment group); dose withholding (30% in the SC treatment group compared 
with 39% in the IV treatment group); or cycle delay (20% in the SC treatment group 
compared with 34% in the IV treatment group). Serious adverse events were similar 
between the 2 treatment groups (36% in the SC treatment group and 35% in the IV 
treatment group). Deaths during treatment (within 30 days of last dose) were 5% in the 
SC treatment group and 7% in the IV treatment group.  
The SC treatment group reported a lower incidence in several adverse events 
associated with VELCADE toxicity. The incidence of peripheral neuropathy events (all 
Grades) was 38% in the SC treatment group and 53% in the IV treatment group; the 
incidence of Grade 2 peripheral neuropathy events was 24% in the SC treatment 
group and 41% in the IV treatment group; and the incidence of Grade 3 peripheral 
neuropathy event was 6% in the SC treatment group and 16% in the IV treatment 
group. There also appeared to be a trend towards lower incidence in gastrointestinal 
adverse events (37% for SC and 58% for IV, predominantly due to differences in Grade 
1-2 abdominal pain, diarrhea, and dyspepsia); as well as a 5% difference in incidence 
of Grade 3 and 4 hematology laboratory results in the SC treatment group compared 
with the IV treatment group for WBC (8% in the SC treatment group compared with 18% 
in the IV treatment group), neutrophil count (22% in the SC treatment group compared 
with 28% in the IV treatment group) and platelets (18% in the SC treatment group 
compared with 23% in the IV treatment group). 
Local tolerability of SC administration was acceptable. Nine (6%) subjects reported a 
local reaction to SC administration as an adverse event. Eighty-five (58%) subjects in 
the SC treatment group reported at least 1 local injection site reaction. The most 
common local injection site reaction was redness which was reported in 84 (57%) 
subjects. The majority of subjects with worst injection site reactions were assessed as 
mild (38%) or moderate (18%). Only 2 (1%) subjects were reported as having severe 
injection site reactions. All local site reactions resolved completely and rarely led to 
treatment modifications. 
In conclusion, the SC administration of VELCADE has good local tolerance. The 
systemic safety profile for the SC administration of VELCADE was associated with a 
lower incidence of Grade 3 adverse events, and treatment modifications 
(discontinuations and dose reductions). In particular, there was a lower incidence of 
peripheral neuropathy NEC reportedxxiv.  
 


 
 
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27
3.0. 
PATIENT SELECTION 
INCLUSION CRITERIA: 
1. Voluntary signed informed consent before performance of any study-related 
procedure not part of normal medical care, indicating that that the patient is aware of 
the investigational nature of the study in keeping with the policies of MDACC and 
with the understanding that consent may be withdrawn by the subject at any time 
without prejudice to future medical care. 
2. Presence of phosphorylated p65 NF-kB component in at least 5% of bone marrow 
cells 
3. Age ≥ 18 years of age at time of signing consent 
4. Confirmed MDS by bone marrow biopsy according to WHO or FAB criteria21. 
5. Classification by the IPSS as low or intermediate-1 risk MDS according to 
cytogenetics, blood cytopenias and % bone marrow blasts within 28 days of the first 
dose of treatment in this study. 
6. Patients must have received at least one prior therapy for MDS. Patients could have 
received transplant for MDS 
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2. 
8. Adequate liver function:  Total bilirubin ≤ 1.5 × the upper limit of normal (ULN), 
unless presence of Gilbert’s Syndrome. Aspartate aminotransferase (AST) and/or 
alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5.0 x ULN if hepatic involvement is 
present as determined by the investigator 
9. Adequate renal function: Serum creatinine ≤ 2 mg/dL or a calculated creatinine 
clearance of ≥ 50 mL/min (using the Cockcroft and Gault method). 
10. Male patients, even if surgically sterilized (ie, status postvasectomy), who agree to 
practice effective barrier contraception during the entire study treatment period and 
through 30 days after the last dose of study treatment, or agree to completely 
abstain from heterosexual intercourse  
11. Female patients who are postmenopausal for at least 1 year before the Screening 
visit, or are surgically sterile, or if they are of childbearing potential, must have a 
negative pregnancy test within 72 hours of treatment start date and agree to practice 
2 effective methods of contraception, at the same time, from the time of signing the 


 
 
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28
informed consent through 30 days after the last dose of study treatment, OR agree 
to completely abstain from heterosexual intercourse 
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory 
tests and other study procedures. 
 
EXCLUSION CRITERIA 
1. Significant medical, psychiatric, cognitive or other conditions that may compromise 
the patient's ability to understand the patient information, to give informed consent, 
to comply with the study protocol, or to complete the study. 
2. Any severe concurrent disease or condition (including active, uncontrolled systemic 
infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac 
arrhythmia) that, in the judgment of the Investigator, would make the patient 
inappropriate for study participation. 
3. Pregnant or lactating females. 
4. Patient has  Grade 2 peripheral neuropathy  
5. Patient had myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure, 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 
must be documented by the investigator as not medically relevant. 
6. Patient has hypersensitivity to bortezomib, boron, or mannitol 
7. Current diagnosis of  another malignancy, with the exception of complete resection of basal 
cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk 
prostate cancer after curative therapy. 
8. Treatment with other investigational agents, chemotherapy, or immunotherapy  within 14 
days of the start of this trial and throughout the duration of this trial. 
9. Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require 
concurrent radiotherapy (which must be localized in its field size) should be deferred until 
the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy. 
 
4.0 
TREATMENT PLAN 
Overview 


 
 
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29
This open-label, Phase II study is designed to determine the clinical activity, safety and 
tolerability of Bortezomib in patients with low or intermediate-1 risk MDS. All patients will 
be registered through Protocol Data Management System (PDMS) or CORe. 
 
Schedule of administration Cycle 1: 
Bortezomib will be administered via subcutaneous route at a dose of 1.3 mg/m2 on days 
1, 4, 8 and 11 of a 21 day cycle. A course of treatment will be approximately 21 days. 
The dose and schedule is adapted based on PK and safety data for subcutaneous 
Bortezomib as published by Moreau et al22.  
 
Subsequent cycles:  
Patients will receive the first course of therapy without interruption regardless of degree 
of myelosuppression.  Patients can continue to receive therapy for a maximum of 2 
years if indicated (see below “Duration of therapy”). After the first course of therapy, 
interval between cycles of therapy can be spaced out at the discretion of the treating 
physician, although a schedule as close to possible as the proposed one will be 
attempted. If prolonged myelosuppression is observed (defined by an absolute 
neutrophil (ANC) count of less than 1 x109/L and a platelet count of less 30 x109/L for 
more than 42 days with evidence of a hypocellular marrow (marrow cellularity less than 
5% without evidence of recurrent MDS) subsequent courses of bortezomib will be given 
at the next lower dose, once the counts recover. Count recovery will be considered if 
the ANC is 1 x109/L, platelets more than 50 x109/L. In the rest of potential clinical 
situations, subsequent courses of therapy will be administered at the discretion of the 
treating physician.  
 
Cycles will be repeated as long as possible until toxicity or lack of response for at least 
6 cycles of therapy. The dose and schedule is adapted from Moreau et al22. In that 
study, the median number of cycles was 8 (range 1 to 10). 
 
Duration of Therapy 


 
 
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30
In the absence of treatment delays due to adverse events, treatment may continue up to 
2 years until one of the following criteria applies: 
a) Clinically significant progressive disease 
b) Possibility of undergoing allogeneic bone marrow transplantation 
c) Clinically significant intercurrent illness that prevents further administration of 
treatment 
d) Patient request or 
e) General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in the judgment of the investigator or treating 
 
5.0 
DOSING DELAYS/ DOSE MODIFICATIONS: 
Dose modifications will be based on guidelines shown in Table 2 
Throughout the study treatment period, the patient will be evaluated for possible 
toxicities that may have occurred after the previous dose(s).  Toxicities are to be 
assessed according to the NCI Common Toxicity Criteria for Adverse Events 
(CTCAE), Version or 4.0 (as preferred by your institution; 
http://ctep.cancer.gov/reporting/ctc.html). 
 
Dose delay window is +2 days for doses 4,8, and 11. There must be at least 72 hours 
between each dose of bortezomib. 
 
All previously established or new toxicities observed any time are to be managed as 
described in Table 3 1.  Neuropathic pain and peripheral sensory neuropathy are to be 
managed as described in Table 4. 
 
Table 2. Bortezomib dose de-escalation. Clinically significant treatment related 
toxicity and dose management: 
Toxicity 
Grade 
Management/Action 


 
 
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Toxicity 
Grade 
Management/Action 
1 or 2 
No change required.  If the toxicity persists at Grade 1 or 2, then 
reduction to a lower dose level is allowed according to 
Investigator judgment and likelihood that the toxicity is related to 
bortezomib. 
3 
Hold treatment. Treatment may resume if toxicity is resolved to 
Grade ≤ 1 or returns to baseline. If the toxicity resolves within 7 
days, bortezomib may be resumed at the same level or at the 
next lower dose level at the discretion of the Investigator.Toxicity 
lasting more than 7 days will require dose reduction to the next 
lower dose level. 
4 
Hold treatment.  Treatment may resume if toxicity is resolved to 
Grade ≤ 1 or returned to baseline at the discretion of the 
Investigator.  Treatment will be reduced by two dose levels from 
the level at which the toxicity was observed. If Grade 4 toxicity 
occurs in spite of two dose level reduction, the patient should be 
discontinued from the study. 
 
Table 3 below summarizes the dose reduction schema to be followed in this study. 
Patients that require reduction of more than 2 dose levels will be removed from the 
study. 
 
Table 3. Dose reduction levels for bortezomib: 
Starting dose level 
1.3 mg/m2 
Dose level -1 
1.0 mg/m2 
Dose level -2 
0.7 mg/m2 
 
Clinically significant toxicity management 
Toxicity 
Grade 
Action 
Lymphopenia 
Any 
None 


 
 
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32
Nonhematological toxicity 
3 
Hold bortezomib 
therapy 
Hematological Toxicity 
4 
Hold bortezomib 
therapy 
 
For any clinically significant and nonhematologic 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 platelet value of 30 
k/uL, and neutrophil value of 1 x 103  
Once bortezomib is reduced for any toxicity, the dose may not be re-escalated. 
If after bortezomib has been held, the toxicity does not resolve, then bortezomib must 
be discontinued. 
If the toxicity resolves, as described above, bortezomib may be restarted at the same 
schedule the patient was on prior to holding therapy, and the dose must be reduced by 
approximately 25% as follows: 
 If the patient was receiving 1.3 mg/m2, reduce the dose to 1 mg/m2. 
 If the patient was receiving 1 mg/m2, reduce the dose to 0.7 mg/m2. 
If the patient was receiving 0.7 mg/m2, discontinue drug. 
Patients who experience bortezomib-related neuropathic pain or peripheral sensory 
neuropathy are to be managed as presented in Table 4.  Once the dose is reduced for 
peripheral neuropathy, the dose may not be re-escalated. 
Table 4   
Management of Patients With bortezomib-Related Neuropathic 
Pain and/or Peripheral Sensory or Motor Neuropathy 
Severity of Peripheral Neuropathy 
Signs and Symptomsa  
Modification of Dose and Regimen 
Grade 1 (asymptomatic; loss of deep 
tendon reflexes or parasthesias) 
without pain or loss of function 
No action 
Grade 1 with pain or Grade 2 
(moderate symptoms; limiting 
Reduce bortezomib 1.0 mg/m2 


 
 
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Table 4   
Management of Patients With bortezomib-Related Neuropathic 
Pain and/or Peripheral Sensory or Motor Neuropathy 
Severity of Peripheral Neuropathy 
Signs and Symptomsa  
Modification of Dose and Regimen 
instrumental Activities or Daily Living 
[ADL]b) 
Grade 2 with pain or Grade 3 (severe 
symptoms; limiting self care ADLc) 
Withhold bortezomib therapy until toxicity 
resolves. When toxicity resolves reinitiate 
with a one dose level reduced dose of  
bortezomib. 
Grade 4 (life-threatening 
consequence; urgent intervention 
indicated) 
Discontinue bortezomib 
 
Source:  bortezomib USPI issued January 2012. 
Abbreviations: ADL = activities of daily living 
a   Grading based on NCI Common Terminology Criteria for Adverse Events 
(CTCAE) v4.0. 
b   Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, 
using telephone, managing money, etc 
c   Self care ADL: refers to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden. 
 
Patients with mild hepatic impairment (bilirubin ≤ 1.5  ULN) do not require a starting 
dose adjustment.  Please note that patients with bilirubin levels > 1.5 ULN are excluded 
from enrollment in this protocol unless Gilbert’s Syndrome is present.  If a patient 
develops  study drug related moderate or severe hepatic impairment with bilirubin ≥ 
Grade 2 (> 1.5 -3.0 X ULN) while on study, the investigator should hold Bortezomib until 
the toxicity returns to < Grade 2. Restarting Bortezomib at the next lower dosed level 
could be considered at the Investigator’s discretion and following exclusion of  
Bortezomib-induced liver impairment and careful consideration of liver disease due to 
other causes, such as, but not limited to, active infection and leukemia-related liver 
disease. 


 
 
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Neurotoxicity-Directed Questionnaire 
The neurotoxicity-directed questionnaire (see Appendix F) is a useful tool for 
determining the presence and intensity of neuropathic pain and/or peripheral 
neuropathy from the patient’s perspective.  It is not a tool intended for direct scoring and 
toxicity grading.  Neuropathic symptoms are more prominent than abnormalities on the 
clinical examination.  After the patient completes the neurotoxicity-directed 
questionnaire, the questionnaire should be reviewed to assist with the evaluation of the 
onset and intensity of peripheral neuropathy and other neurotoxicities that may possibly 
require intervention or dose modification. 
 
6.0 
AGENT FORMULATION AND PROCUREMENT 
SC Bortezomib will  be provided by Millennium. This is an FDA approved agent for 
patients with multiple myeloma.  
Bortezomib Administration  
Drug will be administered only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s).  Patients may be treated on an outpatient 
basis, if possible. 
The drug will be prepared under the supervision of a pharmacist, or appropriately 
qualified and trained personnel.  The amount (in mg) of drug to be administered will be 
determined based on body surface area.  Body surface area is to be calculated based 
on body weight using a standard nomogram or calculation.  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 within a cycle, as determined by an 
unscheduled weight assessment, then the patient’s dose should be recalculated at that 
time based on clinical judgment. 
There must be at least 72 hours between each dose of bortezomib. 
INTRAVENOUS AND SUBCUTANEOUS ROUTE OF ADMINISTRATION HAVE 
DIFFERENT RECONSTITUTED CONCENTRATIONS. CAUTION SHOULD BE USED 
WHEN CALCULATING THE VOLUME TO BE ADMINISTERED. 


 
 
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SUBCUTANEOUS ADMINISTRATION:  
Drug is available in sterile, single use vials containing 3.5 mg of bortezomib.  Each vial 
of bortezomib for Injection should be reconstituted under a laminar flow biological 
cabinet (hood) within eight hours before dosing with 1.4 mL of normal (0.9%) saline, 
Sodium Chloride Injection USP, so that the reconstituted solution contains bortezomib 
at a concentration of 2.5 mg/mL for subcutaneous administration.  
Subcutaneous Administration Precautions:  
 The drug quantity contained in one vial (3.5 mg) may exceed the usual dose 
required.  Caution should be used in calculating the dose to prevent overdose.  
 When administered subcutaneously, sites for each injection (thigh or abdomen) 
should be rotated.   
 New injections should be given at least one inch from an old site and never into 
areas where the site is tender, bruised, erythematous, or indurated.  
 If local injection site reactions occur following bortezomib administration 
subcutaneously, a less concentrated bortezomib solution (1 mg/mL instead of 2.5 
mg/mL) may be administered subcutaneously.  Alternatively, the IV route of 
administration should be considered.  
 In clinical trials of bortezomib IV, local skin irritation was reported in 5% of 
patients, but extravasation of bortezomib was not associated with tissue damage. 
In a clinical trial of subcutaneous bortezomib, a local reaction was reported in 6% 
of patients as an adverse event, mostly redness.  
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. 


 
 
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Treatment Compliance 
All drug will be administered to eligible patients under the supervision of the investigator 
or identified subinvestigator(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 Appendix), total drug 
administered in milliliters and milligrams, and date and time of administration.  Any 
discrepancy between the calculated dose and dose administered and the reason for the 
discrepancy must be recorded in the source documents. 
Precautions and Restrictions 
It is not known what effects bortezomib has on human pregnancy or development of the 
embryo or fetus.  Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner.  
Nonsterilized female patients of reproductive age and male patients should use effective 
methods of contraception through defined periods during and after study treatment as 
specified below. 
Female patients must meet 1 of the following: 
 Postmenopausal for at least 1 year before the screening visit, or 
 Surgically sterile, or 
 If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing the informed consent form through 
30 days after the last dose of bortezomib, or agree to completely abstain from 
heterosexual intercourse. 
It is strongly recommended that at least 1 of these 2 methods be highly effective (see 
examples below). 
Highly effective methods 
Other effective methods (barrier 
methods) 
Intra-uterine devices (IUD) 
Latex condom 
Hormonal contraceptives (birth control 
pills/oral contraceptives, injectable 
contraceptives, contraceptive patches, 
or contraceptive implants) 
Diaphragm with spermicide 
Cervical cap 
Sponge 


 
 
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If one of the highly effective methods cannot be used, using 2 effective methods 
at the same time is recommended.  
 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of 
the following: 
 
Practice effective barrier contraception during the entire study treatment period and 
through a minimum of 30 days after the last dose of study drug, or completely abstain 
from heterosexual intercourse. 
 
6.1 
Concomitant therapies: 
a) Anti-emetic therapy 
Prophylactic and therapeutic treatment for nausea and vomiting is 
recommended.  
b) Anti-Diarrheal Therapy 
Treat study treatment-related diarrhea with loperamide 4 mg followed by 2 mg 
after each loose stool up to a maximum of 16 mg daily. Use alternate 
approaches in patients intolerant of loperamide. Consider prophylactic 
loperamide if previous therapeutic treatment was required in same or 
previous patients. 
c) Transfusion to maintain Hgb > 8 gm/dL and platelet count > 10,000/_L is 
recommended. Higher levels may be targeted if clinically appropriate. 
d) G-CSF may be used in cases of neutropenia and suspected or documented 
infection at physician’s discretion. Erythropoietin and darbepoietin are not 
permissible. 
e) Tumor lysis syndrome Monitoring, prophylactic and therapeutic treatment for 
tumor lysis syndrome is recommended as per institutional criteria. 
f) Infection prophylaxis. Prophylaxis with oral antimicrobial agents is permitted 
for neutropenic patients. 
g) Investigators should consider using antiviral prophylaxis in subjects being 
treated with bortezomib. 


 
 
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6.2 
Excluded therapies: 
Patients may not receive other investigational agents, chemotherapy, or immunotherapy 
not included in this trial, within 14 days of the start of this trial and throughout the 
duration of this trial. Hydroxyurea is not allowed in this group of patients. 
 
7.0 
CORRELATIVE STUDIES 
We will perform exploratory analysis of the effect of SC bortezomib in patients with 
lower risk MDS. In particular we will analyze phosphor-p65  and obtain samples for 
DNA, RNA, and protein analysis approximately at baseline, cycle 1 and 3 day 21. This 
will be performed in the laboratory of Dr Carlos Bueso-Ramos in Hematopathology 
using standard accepted immunocytochemistry techniques.  
 
8.0 
PATIENT EVALUATION 
Pretreatment: 
Results from tests performed as standard of care up to 28 days prior to study entry can 
be used for determining eligibility and establishing baseline measurements. Any 
clinically significant abnormal results (except for bone marrow aspiration) should be 
repeated within 48 hours of beginning therapy to establish a baseline. 
 A complete history and physical exam including height, weight, and vital signs 
(blood pressure, heart rate, breathing rate, and temperature), documentation of 
all measurable disease, and performance status (PS) should be performed 72 
hours before initiation of study, and subsequently as indicated. 
 Document adverse event assessment and concomitant medications as far as 
traceable. 
 CBC, platelet count, creatinine, total bilirubin, SGPT and/or SGOT, potassium 
and blood or urine pregnancy test (when indicated) should be performed 72 
hours before initiation of study. Pregnancy testing will be conducted for any 
female that is of childbearing age that has not been surgically sterilized or without 
a menses for 12 consecutive months. 
 Bone marrow aspirate and/or biopsy during the last 28 days preceding study 
initiation. 


 
 
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 Cytogenetics will be obtained at baseline, if abnormal this will be repeated with 
Cycle 1 day 21 bone marrow aspirate and/or biopsy and at the time of response 
as indicated. 
 12 lead EKG 
 Pretreatment correlative studies if patient signed for them during consent 
process. 
 
During Treatment: 
 CBC, platelet count, creatinine, SGPT and/or SGOT and total bilirubin weekly 
during first course of therapy, and then prior to each course of therapy. 
 Document adverse event assessment and concomitant at each clinic visit. 
 Bone marrow aspiration and/or biopsy will be performed at the end of Cycle 1 (+/- 
5 days) and of Cycle 3 (+/- 5 days) to assess for response and every 3 months 
thereafter as per physicians discretion. Earlier evaluations are allowed as 
clinically indicated. 
 
End-of-Study: 
Thirty days following the last dose of study drug: 
 CBC with chemistry 
 Bone marrow aspirate, if clinically indicated (per investigator or treating 
physician) 
 Document adverse event assessment and concomitant medications. 
 
9.0 
STUDY CALENDAR 


 
 
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Study calendar during therapy: 
 
10.0 CRITERIA FOR RESPONSE  
Criteria for response will follow the modified IWG criteria. This is 
summarized in appendix below. Response will include complete 
remission, partial remission, marrow complete remission and any 
CYCLE  1 
CYCLE 2 - 
Subsequent 
Cycles  
CYCLE 3 
End of 
study 
PreTx W1 
W2 
W3 
D1 
D21 
Complete history, 
physical exam 
including height, 
weight, vital signs, 
and PS 
X 
X 
 
Concomitant 
medication, adverse
event assessment 
 
Continuous 
 
CBC1,3 
X 
X 
X 
X 
X 
 
X 
Chemistries3 
X 
X 
X 
X 
X 
 
X 
Pregnancy test3 
X 
 
EKG3 
X 
 
Bone marrow 
aspirate and/or 
biopsy 2,3 
 
X 
X 
 
X 
 
X 
Cytogenetics2,3,4 
X 
X 
X 
X 
 
PreTx:pretreatment (within 72 hrs unless noted otherwise); W:week; D:day  
1    CBC/diff/platelets; Chem: creatinine, T. bili, SGPT and/or SGOT, potassium 
2    Baseline & repeated on Cycle 1 Day 21 
3    all 5 +/- days 
4 Cytogenetics will be repeated if abnormal at baseline 


 
 
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hematological improvement achieved any time during the duration 
of the therapy. 
 
Proposed modified International Working Group response criteria for altering 
natural history of MDS7  
 Category   
Response criteria (responses must last at least 4 wk)   
 Complete remission   
Bone marrow: 5% myeloblasts with normal maturation of all 
cell lines*   
  
Persistent dysplasia will be noted*    
  
Peripheral blood    
  
   Hgb 11 g/dL   
  
   Platelets 100 x 109/L   
  
   Neutrophils 1.0 x 109/L    
  
   Blasts 0%   
 Partial remission   
All CR criteria if abnormal before treatment except:   
  
Bone marrow blasts decreased by 50% over pretreatment 
but still > 5%   
  
Cellularity and morphology not relevant   
 Marrow CR    
Bone marrow: 5% myeloblasts and decrease by 50% over 
pretreatment    
  
Peripheral blood: if HI responses, they will be noted in 
addition to marrow CR    
 Stable disease   
Failure to achieve at least PR, but no evidence of 
progression for > 8 wks   
 Failure   
Death during treatment or disease progression characterized 
by worsening of cytopenias, increase in percentage of bone 
marrow blasts, or progression to a more advanced MDS 
FAB subtype than pretreatment   


 
 
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 Relapse after CR or PR   At least 1 of the following:   
  
   Return to pretreatment bone marrow blast percentage   
  
   Decrement of 50% from maximum remission/response 
levels in granulocytes or platelets   
  
   Reduction in Hgb concentration by 1.5 g/dL or 
transfusion dependence   
 Cytogenetic response   
Complete   
  
   Disappearance of the chromosomal abnormality without 
appearance of new ones   
  
Partial   
  
   At least 50% reduction of the chromosomal abnormality   
 Disease progression   
For patients with:   
  
   Less than 5% blasts: 50% increase in blasts to > 5% 
blasts   
  
   5%-10% blasts: 50% increase to > 10% blasts   
  
   10%-20% blasts: 50% increase to > 20% blasts   
  
   20%-30% blasts: 50% increase to > 30% blasts   
  
Any of the following:   
  
   At least 50% decrement from maximum 
remission/response in granulocytes or platelets   
  
   Reduction in Hgb by 2 g/dL   
  
   Transfusion dependence   
 Survival   
Endpoints:   
  
   Overall: death from any cause   
  
   Event free: failure or death from any cause   
  
   PFS: disease progression or death from MDS   


 
 
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43
  
   DFS: time to relapse   
  
   Cause-specific death: death related to MDS   
 
Table 6. Proposed modified International Working Group response criteria for 
hematologic improvement7  
 
 Hematologic 
improvement*   
 Response criteria (responses must last at least 
8 wk)    
 Erythroid response 
(pretreatment, < 11 g/dL)   
 Hgb increase by 1.5 g/dL   
  
 Relevant reduction of units of RBC transfusions by 
an absolute number of at least 4 RBC transfusions/8 
wk compared with the pretreatment transfusion 
number in the previous 8 wk. Only RBC transfusions 
given for a Hgb of 9.0 g/dL pretreatment will count 
in the RBC transfusion response evaluation    
 Platelet response 
(pretreatment, < 100 x 109/L)   
 Absolute increase of 30 x 109/L for patients starting 
with > 20 x 109/L platelets   
  
 Increase from < 20 x 109/L to > 20 x 109/L and by at 
least 100%    
 Neutrophil response 
(pretreatment, < 1.0 x 109/L)   
 At least 100% increase and an absolute increase > 
0.5 x 109/L    
 Progression or relapse after 
HI    
 At least 1 of the following:   
  
     At least 50% decrement from maximum response 
levels in granulocytes or platelets   
  
     Reduction in Hgb by 1.5 g/dL   
  
     Transfusion dependence   
 
11.0 CRITERIA FOR REMOVAL FROM THE STUDY 
This will include: 
 
Progressive disease 


 
 
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 
Possibility of undergoing allogeneic bone marrow transplantation 
 
Intercurrent illness that prevents further administration of treatment 
 
Patient request 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
12.0 STATISTICAL CONSIDERATIONS 
General Description: 
This is a Phase II open-label, efficacy and toxicity study of SC bortezomib in subjects 
with low and int-1 myelodysplastic syndrome.  The primary efficacy outcome is the 
overall response rate based mainly on hematologic improvement defined by IWG but of 
course could include complete remission, partial remission and marrow complete 
remission.  
 
Efficacy monitoring: 
A maximum of 40 evaluable patients will be enrolled, but the study will be stopped early 
if the data suggest that: 
   
                                      Pr(<0.15|data)>0.95 
 
Here  is the overall response (OR) rate. Since currently the standard practice is to put 
these patients on observation, an OR rate of about 15% is worth considering. We 
assume the OR rate has a prior Beta distribution (0.3, 1.7) with mean of 0.15 and 
variance of 0.0425. The study will be stopped early if: 
 
(The number of patients who hematological improvement) / (The number of patients 
evaluated)  0/8, 1/24, 2/37, 3/40 
 
That is, if at any time during the study we determine that there is a greater than 95% 
chance that the average OR rate is less than 15%, we will terminate the study. 
 
The operating characteristics of this design are as follows: 


 
 
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45
 Operating characteristics of response (based on 10000 simulations) 
True OR 
Rate 
Early Stopping  
Probability 
Average 
sample size 
achieved 
Stopping boundaries 
0.05 
0.85 
 16.6 
 0 /8 
 1/24 
 2 /37 
 3/40 
0.10 
0.54 
 25.0 
0.15 
0.31 
 30.8 
0.20 
0.18 
34.5 
0.30 
0.06 
38.1 
0.40 
0.02 
39.46 
0.50 
0.004 
39.88 
0.60 
0.0007 
39.97 
 
Toxicity monitoring 
Evidence of Toxicity will be monitored closely in all patients. The study will be terminated if Pr 
(grade 3 or higher Toxicity >0.15|data)>0.95. Table 10 shows the simulation of the trial. 
The treatment will be stopped if all the 2 out of first 2 patients experience clinically 
significant drug related grade 3 or higher toxicity, or  3 out of 4, or  4 out of 7, or  5 
out of 11, or  6 out of 15, or  7 out of 19, or  8 out of 23, or  9 out of 28, or  10 out 
of 32, or  11 out of 37. 
 
Operating characteristics of toxicities (based on 10000 simulations) 
True  
Probabili
ty 
Early 
Stopping  
Probability 
Average 
sample size 
achieved 
Stopping boundaries 
0.05 
0.004 
39.9 
 2 /2 
 3 /4 
 4 /7 
0.10 
0.03 
39.1 
0.15 
0.11 
37.0 


 
 
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46
Operating characteristics of toxicities (based on 10000 simulations) 
0.20 
0.29 
32.9 
 5 /11 
 6 /15 
 7/19 
 8/23 
9 /28 
10 /32 
11/37 
0.30 
0.77 
20.9 
 
0.40 
0.97 
11.8 
 
0.50 
1.0 
7.3 
 
 
Statistical methods: 
Data analysis will be performed using SAS or S-plus, as appropriate. The proportion of 
patients having hematologic improvement and the proportion of patients having grade 3 
or higher toxicities will be estimated by a Bayesian posterior credible interval. If the 
study is completed with 40 patients and there are 6 patients with hematologic 
improvement, a 90% posterior credible interval for the average rate of hematologic 
improvement will be 7% to 25%.  
 
13.0 PROTOCOL ADMINISTRATION 
Protocol specific data will be entered into PDMS/CORe. 
 
Protocol amendments: 
Changes to the protocol will be made only when protocol amendments have been 
signed by the principal investigator and approved by the ethics committee of 
MDAnderson Cancer Center. 
 
Archival of data: 
All patient data (including source data) generated in connection with this study will be 
kept in the archives of the MDACC in accordance with 21 CFR 312.62. All data will be 


 
 
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47
available for inspection by company representatives of the Medical Department and by 
regulatory authorities. 
Product Complaints 
A product complaint is a verbal, written, or electronic expression which implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug 
product.  Individuals who identify a potential product complaint situation should 
immediately contact MedComm Solutions (see below) and report the event.  Whenever 
possible, the associated product should be maintained in accordance with the label 
instructions pending further guidance from a Millennium quality representative. 
A medication error is a preventable event that involves an identifiable patient and that 
leads to inappropriate medication use, which may result in patient harm.  While 
overdoses and underdoses constitute medication errors, doses missed inadvertently by 
a patient do not.  Individuals who identify a potential medication error situation should 
immediately contact MedComm Solutions (see below) and report the event. 
 
For Product Complaints or Medication Errors,  
call MedComm Solutions at 
1-866-835-2233 (US sites and International)  
 
Product complaints and medication errors in and of themselves are not AEs.  If a 
product complaint or medication error results in an SAE, an SAE form should be 
completed and sent to PPD (refer to Appendix B). 
 
 
 


 
 
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14.0 References: 
 
1. 
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