Clinical trial NCT01736943
Conditions: Acute Myelogenous Leukemia
Keywords: Bortezomib Doxil
Sponsor: Joseph Tuscano
Start date: 2012-12-19; Completion date: 2019-05-20
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether bortezomib in combination with doxil/lipodox is effective in the treatment of Acute Myeloid Leukemia.

Detailed description:
Acute myeloid leukemia (AML) remains largely incurable despite advances that have been made in recent years into increasing the complete response (CR) rates. In elderly patients (over the age of 60), CR rates are lower, 40 to 50%, and long term disease-free and overall survival is less than 10%. The therapeutic options for relapsed/refractory AML are significantly limited. Bortezomib has shown promising activity in patients with advanced hematologic malignancies, including those with leukemia and non-Hodgkin's lymphoma.

Given the available data suggesting efficacy of bortezomib in combination with doxil in patients with relapsed multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and Non Hodgkin's lymphoma (NHL) as well as the known sensitivity of AML to anthracyclines and in vitro data demonstrating the sensitivity of multiply resistant AML cells to bortezomib, we are proposing the use of this combination in patients with relapsed/refractory AML or elderly patients who are not candidates for standard induction therapy.

Using the subcutaneous formulation of bortezomib would provide patients with reduced neurotoxicity and easier schedule due to decreased time in the infusion room and it would decrease overall cost of care.

Arms: arm 1: Bortezomib will be given subcutaneously at 1.5mg/m2 on days 1, 4, 8 and 11 of a 3 week cycle. Doxil will be administered once every three weeks as a single intravenous infusion at a dose of 40 mg/m2 (day 4 of each cycle).
Interventions: intervention 1: Bortezomib intervention 2: Doxil
Intervention descriptions: intervention 1: Bortezomib will be given twice a week subcutaneously (under the skin) for two weeks in every 3 week cycle. intervention 2: Doxil or LipoDox will also be given through a venous catheter (inside your vein). Doxil or LipoDox will be given over 60 to 90 minutes on Day 4 of every 21-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
University of California Davis 
 
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CLINICAL STUDY PROTOCOL  
 
Phase II Trial of the Combination of Decitabine, SQ Bortezomib and Pegylated Liposomal 
Doxorubicin (PLD or Doxil ® or LipoDox®) for the Treatment of Patients with 
Relapsed/Refractory Acute Myelogenous Leukemia (AML) 
 
Protocol Number: 
UCDCC#230 
Indication: 
Acute Myeloid/Myelogenous Leukemia  
Phase: 
2  
IND Number: 
114,428 
EudraCT Number: 
 
Therapeutic Area: 
Oncology  
 
 
Protocol History 
Original 
 
11/03/2011 
Amendment 1 
 
05/29/2012 
Amendment 2 
 
10/17/2012 
Amendment 3 
 
12/26/2012 
Amendment 4 
 
02/26/2013 
Amendment 5 
 
02/04/2014 
Amendment 6  
Amendment 7 
Amendment 8 
Amendment 9  
Amendment 10 
Amendment 11 
 
08/14/2014 
09/21/2015 
01/24/2016 
03/07/2016 
12/26/2016 
04/03/2017 
 
 
Investigator and Study Center: 
 
Joseph Tuscano, MD 
UC Davis Medical Center 
4501 X Street 
Sacramento, CA 95817  
 
Co-Investigator: 
 
Brian Jonas, MD 
 
Biostatistician:  
 
Laurel Beckett, Ph.D 
This is an investigator-initiated study.  The principal investigator, Joseph Tuscano MD, (who 
may also sometimes be referred to as the sponsor-investigator), is conducting the study 
and acting as the sponsor. Therefore, the legal/ethical obligations of the principal 
investigator include both those of a sponsor and those of an investigator. 
 
*VELCADE is the exclusive trademark of Millennium Pharmaceuticals, Inc., (Millennium) 
registered in the United States and internationally.


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PROTOCOL SUMMARY 
Title 
Phase II Trial of the Combination of Decitabine, SQ Bortezomib and Pegylated Liposomal 
Doxorubicin (PLD or Doxil® or LipoDox®) for the Treatment of Patients with 
Relapsed/Refractory Acute Myelogenous Leukemia (AML) 
 
Objectives 
The primary objectives of this study are to: 
• 
Assess response rate and progression free survival (PFS) 
 
The secondary objectives of this study are to: 
• 
Assess overall survival and toxicity 
Patient Population 
Patients with AML who have either relapsed or refractory disease as well as previously 
untreated patients with AML who are not candidates for standard induction therapy  
 
Specific inclusion and exclusion criteria are detailed in Section 3.2. 
Number of Patients 
29. Fifteen subjects were enrolled prior to amendment 7, two subjects were enrolled per 
amendment 9 and up to 12 additional subjects will be enrolled per amendment 10 (detailed 
in Section 5.2).  
Study Design and Methodology 
Phase II, open label  
Treatments Administered 
Induction: 
Decitabine 20mg/m2 (IV) days 1-10 
Bortezomib: 1.3mg/m2 (SQ) days 5, 8, 12, and 15  
PLD or Doxil® or LipoDox®: 40mg/m2 (IV) day 12  
Patients will receive a minimum of 1 cycle and a maximum of 4 cycles of induction. If there 
is no response or progression after two cycles of induction, they will be taken off the study. 
 
Post-Induction: 
Decitabine 20mg/m2 (IV) days 1-5 
Bortezomib: 1.3mg/m2 (SQ) days 1 and 8  
PLD or Doxil® or LipoDox®: 40mg/m2 (IV) day 12  
Patients will receive continued cycles of post-induction therapy until progression, 
intolerance, transplant or withdrawal of informed consent for a maximum of 12 cycles 
(induction cycles are counted towards this total). 
 
Efficacy Data Collected 
The following evaluations will be conducted to assess the efficacy of decitabine, 
subcutaneous bortezomib and PLD or Doxil® or LipoDox®: 


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• 
Peripheral blood counts 
• 
Bone marrow biopsy (done at baseline, after each cycle of induction until complete 
response (CR) or CR with incomplete count recovery (CRi), and after every six 
cycles of post-induction therapy) 
 
Safety Data Collected 
The following evaluations will be conducted to assess the safety of decitabine, 
subcutaneous bortezomib and PLD or Doxil® or LipoDox®: 
• 
There will be a safety lead-in with the first 6-9 subjects enrolled evaluated for DLTs 
during cycle 1. 
• 
Assess for clinical adverse events every 4 weeks especially assessing for peripheral 
neuropathy, diarrhea, hypotension and tachycardia 
• 
Comprehensive metabolic panel to assess the creatinine, bilirubin, AST and ALT 
levels. At least weekly during induction and every two weeks during post-induction 
therapy.   
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF IN-TEXT TABLES ..................................................................................................6 
LIST OF ABBREVIATIONS ..................................................................................................7 
1. INTRODUCTION AND STUDY RATIONALE ................................................................9 
1.1 Overview of the Disease .............................................................................................9 
1.2 VELCADE® (bortezomib) for Injection ....................................................................10 
1.2.1 Scientific Background .........................................................................................10 
1.2.2 Nonclinical Pharmacology .................................................................................11 
1.2.3 Nonclinical Toxicity .............................................................................................12 
1.2.4 Clinical Pharmacokinetics and Pharmacodynamics ......................................13 
1.2.5 Clinical Experience .............................................................................................15 
1.2.6 Potential Risks of VELCADE .............................................................................20 
1.3.1   
Scientific Background ..................................................................................27 
1.3.2    Nonclinical Pharmacology ..........................................................................28 
1.3.3   
Nonclinical Toxicity ......................................................................................28 
1.3.4   
Clinical Pharmacokinetics and Pharmacodynamics ...............................29 
1.3.5   
Clinical Experience ......................................................................................29 
2. STUDY OBJECTIVES .....................................................................................................38 
2.1 Primary Objectives .....................................................................................................38 
2.2 Secondary Objectives ...............................................................................................38 
3. INVESTIGATIONAL PLAN .............................................................................................38 
3.1 Overall Design and Plan of the Study .....................................................................38 
3.2 Selection of Patients .................................................................................................41 
3.2.1    Inclusion Criteria...........................................................................................41 
3.2.2    Exclusion Criteria .........................................................................................43 
3.3    Study Treatments ...............................................................................................44 
3.3.1  Clinical Trial Materials ......................................................................................44 
3.3.2    Preparation, Handling, Storage, and Destruction of Drugs ...................45 
3.3.3   Dose Modifications and Delays .....................................................................50 
3.3.4  Treatment Assignment .....................................................................................56 
3.3.5 Blinding, Packaging, and Labeling ..................................................................56 
3.3.6    Concomitant Treatment...............................................................................56 
3.3.7 Prohibited Concurrent Therapy ........................................................................57 
3.3.8   
Treatment Compliance ................................................................................57 
3.3.9    Precautions and Restrictions .....................................................................57 
3.4    
Duration of Treatment and Patient Participation ..........................................58 
3.6    
Efficacy ................................................................................................................59 
3.6.1    
Efficacy Measurements ...............................................................................59 
3.6.2    Safety Measurements .................................................................................61 
4. ADVERSE EVENTS ........................................................................................................62 
4.1 Definitions ...................................................................................................................62 
4.1.1 Adverse Event Definition ...................................................................................62 
Adverse Drug Reaction ...............................................................................................62 
4.1.2 Serious Adverse Event Definition .....................................................................63 
4.2 Procedures for Reporting Serious Adverse Events (SAEs) ................................64 


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4.3 Procedures for Reporting Drug Exposure during Pregnancy and Birth 
Events .........................................................................................................................66 
5. STATISTICAL CONSIDERATIONS ..............................................................................66 
5.1 Study Design and Overview of Primary and Secondary Endpoints ..................66 
5.2 Sample Size Estimation/Accrual Rate ....................................................................67 
5.3 Randomization and Stratification Factors ..............................................................67 
5.4 Evaluation of Efficacy ................................................................................................67 
5.5 Evaluation of Safety ...................................................................................................68 
6. ADMINISTRATIVE REQUIREMENTS .........................................................................68 
6.1 Good Clinical Practice ...............................................................................................68 
6.2 Ethical Considerations ..............................................................................................68 
6.3 Patient Information and Informed Consent ............................................................69 
6.4 Institutional Review ....................................................................................................69 
6.5 Patient Confidentiality ...............................................................................................70 
6.6 Protocol Compliance .................................................................................................70 
6.7 On-site Audits .............................................................................................................70 
6.8 Drug Accountability ....................................................................................................71 
6.9 Product Complaints ...................................................................................................71 
6.10 Premature Closure of the Study ............................................................................72 
6.11 Record Retention .....................................................................................................72 
7. REFERENCES .................................................................................................................73 
8. APPENDICES ..................................................................................................................80 
8.1 Study Calendar/Toxicity and Events .......................................................................80 
8.2 Karnofsky Performance Status Scale .....................................................................82 
8.3 Body Surface Area .....................................................................................................83 
8.4 New York Heart Association Classification of Cardiac Disease .........................84 
8.5 Common Terminology Criteria for Adverse Events ..............................................85 
8.6 RTOG/EORTC Late Radiation Morbidity Scoring Scheme .................................86 
Neurotoxicity Assessment Tool .....................................................................................90 
8.7 Package Insert for Doxil ............................................................................................91 
8.8 Package Insert for LipoDox ..........................................................................................92 
http://www.caraco.com/Lipodox/Lipodox-50%20injection-outsert.pdf ............................92 
8.9 Package Insert for Decitabine .......................................................................................93 
http://otsuka-us.com/products/Documents/DACOGEN.PI.pdf ..........................................93 
8.11 Data Submission Schedule .....................................................................................94 
8.12 Pregnancy Form ..........................................................................................................95 
 
 
 
 


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LIST OF IN-TEXT TABLES 
Table 1-1    
Summary of Pharmacokinetic and Pharmacodynamic Parameters Following 
Subcutaneous Injections of VELCADE 1.3mg/m2 Using 2.5mg/ml and 1.0 
mg/mL Solutions…………………………………………………………….........21 
Table 1-2 
Known Anticipated Risks of VELCADE by MedDRA System Organ Class, 
Observed Incidence, and Preferred Term……………………………………..19 
Table 1-3    
Reports of Adverse Reactions From Postmarketing Experience ................. 25 
Table 3-1 
Reconstitution and Final Concentration of  Bortezomib (3.5 mg Vial)..…….32 
Table 3-2    
Toxicity Management .................................................................................. 50 
Table 3-3    
Management of Patients With VELCADE-Related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy .................................................... 52 
 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
°C 
degrees Celsius 
µM 
micromolar 
20S 
20S proteasome subunit 
AE 
adverse event 
ANC 
absolute neutrophil count 
Bc1-2 
B-cell lymphoma-2; a gene that inhibits apoptosis 
BSA 
body surface area 
CAM 
cell adhesion molecules 
cm 
centimeter 
CR 
complete response 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CV 
cardiovascular 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
EBMT 
European Group for Blood and Marrow Transplant 
Emax 
maximum effect 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
ht 
height 
IκB 
I kappa B kinase; cytokine response kinase that activates 
transcription factor NF-kappa b at serine 32 and 36 
ICAM-1 
intercellular adhesion molecule 1 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IL-6 
interleukin-6 
IND 
Investigational New Drug 
IRB 
institutional review board 
IV 
intravenous 
IκBα 
I kappa B alpha-associated protein kinase 
kg 
kilogram 
Ki 
inhibitory constant 
lbs 
pounds 
m2 
square meters 
MCL 
mantle cell lymphoma 


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Abbreviation 
Definition 
mg 
milligram 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
min 
minute 
mL 
milliliter 
MM 
multiple myeloma 
mm3 
cubic millimeters 
mmol 
millimole 
MR 
minor response 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
nCR 
near complete response 
NF-κB 
nuclear factor-κB 
ng 
nanogram 
NHL 
Non-Hodgkin’s lymphoma 
nM 
nanomole 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
overall survival 
P21 
p21(ras) farnesyl-protein transferase 
P27 
cyclin-dependent kinase inhibitor 
P53 
tumor suppressor protein with molecular weight of 53 kDa 
PK 
pharmacokinetics 
PR 
partial response 
SAE 
serious adverse event 
TFI 
treatment free interval 
TNT 
time to next therapy 
TTP 
time to progression 
ULN 
upper limit of normal 
US 
United States 
US FDA 
United States Food and Drug Administration 
USP 
United States Pharmacopeia 
VCAM-1 
vascular cell adhesion molecule 1 
w/w 
weight-to-weight ratio 
wt 
weight 


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1.    
INTRODUCTION AND STUDY RATIONALE 
1.1    Overview of the Disease 
Acute myeloid leukemia remains largely incurable despite advances that have been made 
in recent years into increasing the complete response (CR) rates. In elderly patients (over 
the age of 60), CR rates are lower, 40 to 50%, and long term disease-free and overall 
survival is less than 10%.1 The therapeutic options for relapsed/refractory AML are 
significantly limited. Bortezomib has shown promising activity in patients with advanced 
hematologic malignancies, including those with leukemia and non-Hodgkin’s lymphoma.  
Pre-clinical studies have shown that proteasome inhibition promotes apoptosis of tumor 
cells in part through stabilization of the negative regulator of nuclear factor kappa B (NF-
κB).  Several in-vitro studies have also shown bortezomib to induce apoptosis in human 
AML cells.  In addition a recent phase I study that utilized bortezomib in combination with 
standard induction therapy patients with relapsed/refractory AML was shown to produce 
high response rates with minimal additional toxicity.2 In this study there was no MTD 
established for bortezomib with the highest dose being 1.5mg/m2 given on days 1, 4, 8 and 
11. Anthracyclines, in part, exert anti-tumor activity by inducing an NF-κB driven, anti-
apoptotic process. Laboratory evidence has suggested that activity of the transcription 
factor NF-κB promotes anthracycline resistance.   This particular resistance can be 
overcome when a proteasome inhibitor is given in conjunction with the anthracycline. We 
showed that the combination of bortezomib 1.5mg/m2 on days 1, 4, 8 and 11 with liposomal 
doxorubicin was well-tolerated with 13% of patients having grade 3 neurotoxicity.52 The 
regimen showed modest activity in relapsed/refractory AML patients, with partial remissions 
in 20% of patients and blast count reductions in 79%. 
The hypomethylating agents (HMA), including decitabine, have significant activity in AML 
and have been shown to work primarily through inhibition of DNA methyltrasnferase 
enzymes.53-54 In addition, HMA have been shown to inhibit the NF-kB pathway including 
relocalization of NF-kB to the cytoplasm, likely as an off-target effect through IKK 
inhibition.55-58 Recently, a 10-day dosing schedule of decitabine for AML has demonstrated 
significant activity, with CR rates of 40-64% in untreated older patients and 16% in 
relapsed/refractory patients.59-61 The regimen is well-tolerated with febrile neutropenia, 
infections and myelosuppression most common. The 10-day decitabine regimen was 
combined with bortezomib in a phase I study in relapsed/refractory AML or untreated older 
patients.62 The borezomib dose was escalated to 1.3mg/m2 on days 5, 8, 12 and 15 without 
dose-limiting toxicities. Toxicities were similar to the 10-day decitabine studies, and grade 3 
neurotoxicity related to bortezomib was seen in 3 of 19 patients (all three events were after 
induction). CR was achieved in 50% of untreated and 22% of relapsed/refractory patients. 


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These studies continued decitabine with or without bortezomib until disease progression or 
unacceptable toxicity.53-54,59-62 Based on these studies, there are two ongoing clinical trials 
using the combination of 10-day decitabine and bortezomib with or without additional 
agents (NCT01420926 and NCT01861314). In NCT01420926, three of the bortezomib 
doses are being administered concurrently with the 10-days of decitabine (decitabine days 
2-11 and bortezomib days 1, 4, 8 and 11). 
Using the SC formulation of VELCADE® would provide patients with an easier schedule, 
reduced neurotoxicity due to decreased time in the infusion room and it would decrease 
overall cost of care. 
1.2    VELCADE® (bortezomib) for Injection 
1.2.1    Scientific Background 
VELCADE® (bortezomib) for Injection is a small-molecule proteasome inhibitor developed 
by Millennium Pharmaceuticals, Inc., (Millennium) as a novel agent to treat human 
malignancies.  VELCADE is currently approved by the United States Food and Drug 
Administration (US FDA) 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), VELCADE 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.  VELCADE 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, VELCADE affects multiple signaling 
pathways.  The antineoplastic effect of VELCADE likely involves several distinct 
mechanisms, including inhibition of cell growth and survival pathways, induction of 
apoptosis, and inhibition of expression of genes that control cellular adhesion, migration, 
and angiogenesis.  Thus, the mechanisms by which VELCADE elicits its antitumor activity 
may vary among tumor types, and the extent to which each affected pathway is critical to 
the inhibition of tumor growth could also differ.  VELCADE has a novel pattern of 
cytotoxicity in National Cancer Institute (NCI) in vitro and in vivo assays.3  In addition, 
VELCADE has cytotoxic activity in a variety of xenograft tumor models, both as a single 
agent and in combination with chemotherapy and radiation.4,5,6,7,8,9,10,11,12,13,14,15,16  Notably, 
VELCADE induces apoptosis in cells that over express bcl-2, a genetic trait that confers 
unregulated growth and resistance to conventional chemotherapeutics.17 


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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-α, tumor suppressor protein 
p53, angiogenesis factors, and many others.  VELCADE is thought to be efficacious in 
multiple myeloma via its inhibition of nuclear factor κB (NF-κB) activation, its attenuation of 
interleukin-6 (IL-6)-mediated cell growth, a direct apoptotic effect, and possibly anti-
angiogenic and other effects.18,19,20,21,22,23,24,25 
1.2.2    Nonclinical Pharmacology 
Pharmacokinetic (PK) and pharmacodynamic studies were conducted in the rat and 
cynomolgus monkey.  Upon intravenous (IV) bolus administration, VELCADE displays a 
rapid distribution phase (t½α < 10 minutes) followed by a longer elimination phase (t½β 5-15 
hours).  VELCADE has a large volume of distribution (range 5-50 L/kg).  The plasma PK 
profile is well described by a 2-compartment model. 
The pharmacodynamic action of VELCADE is well established and can be measured 
through an ex vivo assay (20S proteasome activity).26  This assay was used to determine 
the duration of drug effect in lieu of the PK data in the early preclinical toxicology studies as 
well as to set a guide for dose escalation in humans.  Following dosing with VELCADE in 
the rat and cynomolgus monkey, proteasome inhibition in peripheral blood had a half-life 
less than 24 hours, with proteasome activity returning to pretreatment baseline within 
24 hours in monkey and within 48 to 72 hours in rat after a single dose of VELCADE.  
Further, intermittent but high inhibition (> 70%) of proteasome activity was better tolerated 
than sustained inhibition.  Thus, a twice-weekly clinical dosing regimen was chosen in order 
to allow return of proteasome activity towards baseline between dose administrations. 
Subcutaneous administration 
In monkeys, plasma bortezomib tmax generally occurred at 0.117 h following IV dosing and 
0.117 to 0.25 h following SC dosing. After administration of 1.2 mg/m2, peak plasma 
concentration and AUC0-72h attained 124 ng/mL and 141 ng.h/mL following IV 
administration and 113 ng/mL and 211 ng.h/mL following SC administration on the last day 
of dosing, demonstrating a bioavailability close to 100%. Treatment with bortezomib 
induced an inhibition of the whole blood 20S proteasome activity reaching a maximal effect 
between 15 minutes and 1 hour after dosing. The profile of inhibition over time was 
comparable between cycles and similar after subcutaneous and intravenous injections. 


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1.2.3    Nonclinical Toxicity 
Single-dose, IV toxicity studies were conducted with VELCADE in the mouse, rat, dog, and 
monkey to establish the single-dose maximum tolerated dose (MTD).  The MTDs were 
0.25 mg/kg (1.5 mg/m2) and 0.067 mg/kg (0.8 mg/m2) in the 2 most sensitive species, rat 
and monkey, respectively. 
Repeat-dose, multicycle toxicity studies of 3 and 6 months in the rat and 9 months in the 
monkey, each with 8-week recovery periods, were conducted to characterize the chronic 
toxicity of VELCADE when administered by the clinical route and regimen of administration.  
The MTD in the 6-month rat study was 0.10 mg/kg (0.6 mg/m2) and the key target organs 
were the gastrointestinal (GI) tract and hematopoietic and lymphoid systems.  The MTD in 
the 9-month monkey study was 0.05 mg/kg (0.6 mg/m2) and the key target organs were the 
GI tract, hematopoietic and lymphoid systems, peripheral nervous system, and kidney.  Full 
or partial reversibility was observed for each of the toxicities described to date. 
In general, the nature of the toxicity of VELCADE is similar across species, and target 
organs of toxicity in animals have been largely predictive of human toxicity.  The toxicity of 
VELCADE in animals is characterized by a steep dose-response with mortality seen at 
dosages above the MTD.  The cause of death at acutely lethal dosages is considered to be 
related to indirect cardiovascular (CV) effects of hypotension and vascular changes with 
secondary bradycardia and the cause of death in long-term studies has been attributed to 
GI or hematologic toxicity.  The pharmacologic effects of VELCADE on the CV system have 
been extensively characterized and have demonstrated that indirect effects on CV function 
occur only at acutely lethal dosages and are abrogated by routine supportive care. 
Subcutaneous administration 
Repeat dose toxicity of VELCADE administered by subcutaneous and intravenous injection 
(up to 4 cycles of 11 days of VELCADE) was evaluated in cynomolgus monkeys. Each of 
cycles 1, 2 and 3 consisted of dosing on Days 1, 4, 8 and 11, followed by 1 week of 
recovery. VELCADE treatment at 1.2mg/m2 IV or SC induced abnormal feces (soft, liquid 
and/or mucoid), emesis, reduced appetite and decreased activity. Local tolerance was very 
good for SC administration. There were no hematological changes associated with the 
administration of VELCADE SC or IV but slight decreases in total, protein and globulin 
values as well as microscopic changes in the peripheral nervous system, kidneys, bone 
marrow, and immune system of animals were seen. There were no clear differences in the 
incidence and severity of these findings between animals dosed subcutaneously and those 
treated intravenously. 25 


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Additional detailed information regarding the nonclinical pharmacology and toxicology of 
VELCADE may be found in the most recent Investigator’s Brochure. 
1.2.4    Clinical Pharmacokinetics and Pharmacodynamics 
The clinical pharmacology characterization of VELCADE has been determined from phase 
1 studies in subjects with solid tumors and hematological malignancies, and confirmed in 
phase 2 studies in subjects with multiple myeloma. 
VELCADE demonstrates multicompartmental pharmacokinetics.  Following intravenous 
administration of 1.0 mg/m2 and 1.3 mg/m2 dose, the mean first-dose maximum observed 
plasma concentrations of VELCADE were 57 and 112 ng/mL, respectively, in 11 patients 
with MM and creatinine clearance values > 50 mL/min participating in a pharmacokinetics 
study.  In subsequent doses, mean maximum observed plasma concentrations ranged from 
67 to 106 ng/mL for the 1.0-mg/m2 dose and 89 to 120 ng/mL for the 1.3-mg/m2 dose.  The 
mean elimination half-life of VELCADE upon multiple dosing ranged from 40 to 193 hours.  
VELCADE is eliminated more rapidly following the first dose.  Mean total body clearances 
were 102 and 112 L/h following the first dose for doses of 1.0 mg/m2 and 1.3 mg/m2, 
respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1.0 and 
1.3 mg/m2, respectively.  Clinical experience has shown that the change in clearance does 
not result in overt toxicity from accumulation in this multidose regimen in humans. 
In subjects with advanced malignancies, the maximum pharmacodynamic effect (inhibition 
of 20S activity) occurred within 1-hour postdose.  At the therapeutic dose of 1.3 mg/m2 in 
subjects with MM, the mean proteasome inhibition at 1 hour postdose 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 the next scheduled dosing.  In theory, this advantage allows cells to 
recover proteasome activity for normal cellular housekeeping functions between doses. 
The relationship between VELCADE plasma concentrations and proteasome inhibition can 
be described by a maximum effect (Emax) model.  The Emax curve is initially very steep, with 
small changes in plasma VELCADE concentration over the range of 0.5 to 2.0 ng/mL 
relating to large increases in the percent inhibition (0–60%).  After that, a plateau occurs 
where marginal increases of proteasome inhibition are observed in spite of large changes in 
plasma VELCADE concentrations. 


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Subcutaneous administration 
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 1-1). 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 administration.27 


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Table 1-1   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)  
 
1.2.5    Clinical Experience 
To date, more than 436,000 patients have been treated with VELCADE, including patients 
treated through Millennium-sponsored clinical trials, Investigator-Initiated Studies, the US 
NCI Cancer Therapy Evaluation Program (CTEP), and with commercially available drug.  
VELCADE has been commercially available since 13 May 2003. 
The overall goal of the Millennium phase 1 program was to determine the MTD and dose-
limiting toxicity (DLT) of VELCADE in a number of therapeutic settings involving subjects 
with various advanced malignancies.  In a phase 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.28  The toxicity was greatest during the third and fourth weeks of therapy.  In 
the 3-week schedule of VELCADE monotherapy (4 doses, given on Days 1, 4, 8, and 11 of 
a 21-day treatment cycle), the DLT occurred at 1.56 mg/m2/dose (3 subjects with Grade 3 
diarrhea and 1 with peripheral sensory neuropathy).  Therefore, the MTD at this schedule 
was 1.3 mg/m2/dose.  In a 35-day treatment cycle with 4 weekly doses of VELCADE 
monotherapy, the MTD was 1.6 mg/m2/dose and DLT included hypotension, tachycardia, 
diarrhea, and syncope. 
In phase 1 clinical studies, 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.29,30,31,32 


U ni versit y of C alif or ni a D a vis  
 
V E L C A D E ®  ( b ortez o mi b) f or I njecti o n 
Cli nic al St u d y Pr ot oc ol [ U C D C C # 2 3 0]  
 
Versi o n D ate:   0 4/ 0 3/ 1 7  
C o nfi de nti al  
1 6 
T h e s af et y a n d effi c a c y of V E L C A D E i n s u bj e ct s wit h M M w er e i n v e sti g at e d i n t w o p h a s e 2 
cli ni c al  st u di e s,  st u di e s  M 3 4 1 0 0 -0 2 4  ( s u bj e ct s  wit h  fir st  r el a p s e) 3 3  a n d  M 3 4 1 0 0 -0 2 5 
( s u bj e ct s  wit h  s e c o n d  or  gr e at er  r el a p s e  a n d  r efr a ct or y  t o  t h eir  l a st  pri or  t h er a p y). 3 4    I n 
M 3 4 1 0 0 -0 2 5,  2 0 2  h e a vil y  pr etr e at e d  s u bj e ct s  wit h  r efr a ct or y  M M  aft er  at  l e a st  2  pr e vi o u s 
tr e at m e nt s r e c ei v e d V E L C A D E, 1. 3 m g/ m2  o n D a y s 1, 4, 8, a n d 1 1 of a 2 1 -d a y tr e at m e nt 
c y cl e.  T h e E ur o p e a n Gr o u p f or Bl o o d a n d M arr o w Tr a n s pl a nt ( E B M T) r e s p o n s e crit eri a, a s 
d e s cri b e d  b y  Bl a d e 3 5  w er e  utili z e d  t o  d et er mi n e  di s e a s e  r e s p o n s e.    C o m pl et e  r e s p o n s e s 
( C R s) w er e o b s er v e d i n 4 % of s u bj e ct s, wit h a n a d diti o n al 6 % of p ati e nt s m e eti n g all crit eri a 
f or  C R  b ut  h a vi n g  a  p o siti v e  i m m u n ofi x ati o n  t e st.    P arti al  r e s p o n s e  ( P R)  or  b ett er  w a s 
o b s er v e d i n 2 7 % of s u bj e ct s, a n d t h e o v er all r e s p o n s e r at e ( C R, P R, a n d mi n or r e s p o n s e 
[ M R]  c o m bi n e d)  w a s  3 5 %.    S e v e nt y  p er c e nt  of  s u bj e ct s  e x p eri e n c e d  st a bl e  di s e a s e  or 
b ett er.  
T h e p h a s e 3 st u d y ( M 3 4 1 0 1 -0 3 9) 3 6 , al s o r ef err e d t o a s t h e A P E X st u d y, w a s d e si g n e d t o 
d et er mi n e  w h et h er  V E L C A D E  pr o vi d e d  b e n efit  (ti m e  t o  pr o gr e s si o n  [ T T P],  r e s p o n s e  r at e, 
a n d s ur vi v al) t o p ati e nt s wit h r el a p s e d or r efr a ct or y M M r el ati v e t o tr e at m e nt wit h hi g h -d o s e 
d e x a m et h a s o n e. T h e  st u d y  w a s  al s o  d e si g n e d  t o  d et er mi n e  t h e  s af et y  a n d  t ol er a bilit y  of 
b ort e z o mi b  r el ati v e  t o  hi g h -d o s e  d e x a m et h a s o n e,  a n d  w h et h er  tr e at m e nt  wit h  b ort e z o mi b 
w a s  a s s o ci at e d  wit h  s u p eri or  cli ni c al  b e n efit  a n d  q u alit y  of  lif e  r el ati v e  t o  hi g h -d o s e 
d e x a m et h a s o n e.    A  t ot al  of  6 6 9  p ati e nt s  w er e  e nr oll e d  a n d  6 6 3  p ati e nt s  r e c ei v e d  st u d y 
dr u g ( b ort e z o mi b :  3 3 1; d e x a m et h a s o n e:  3 3 2). P ati e nt s r a n d o mi z e d t o V E L C A D E r e c ei v e d 
1. 3  m g/ m 2  I V  p u s h  t wi c e  w e e kl y  o n  D a y s  1,  4,  8,  a n d  1 1  of  a  3-w e e k  c y cl e  f or  u p  t o  8 
tr e at m e nt c y cl e s a s i n d u cti o n t h er a p y, f oll o w e d b y 1. 3-m g/ m
2  V E L C A D E w e e kl y o n D a y s 1, 
8, 1 5, a n d 2 2 of a 5 -w e e k c y cl e f or 3 c y cl e s a s m ai nt e n a n c e t h er a p y.  P ati e nt s r a n d o mi z e d 
t o d e x a m et h a s o n e r e c ei v e d or al d e x a m et h a s o n e 4 0 m g o n c e d ail y o n D a y s 1 t o 4, 9 t o 1 2, 
a n d 1 7 t o 2 0 of a 5 -w e e k c y cl e f or u p t o 4  tr e at m e nt c y cl e s a s i n d u cti o n t h er a p y, f oll o w e d 
b y  d e x a m et h a s o n e  4 0  m g  o n c e  d ail y  o n  D a y s  1  t o  4  of  a  4 -w e e k  c y cl e  f or  5  c y cl e s  a s 
m ai nt e n a n c e  t h er a p y.    T h e  E B M T  r e s p o n s e  crit eri a  w er e  utili z e d  t o  d et er mi n e  di s e a s e 
r e s p o n s e.  T h er e w a s a 7 8 % i n cr e a s e i n T T P f or t h e b ort e z o mi b ar m. M e di a n T T P w a s 6. 2 
m o nt h s  f or  t h e  V E L C A D E  ar m  a n d  3. 5  m o nt h s  f or  t h e  d e x a m et h a s o n e  ar m  ( p  <  0. 0 0 0 1).  
C R + P R w a s 3 8 % wit h V E L C A D E v er s u s 1 8 % wit h d e x a m et h a s o n e ( p <  0. 0 0 0 1).  C R w a s 
6 % wit h b ort e z o mi b v er s u s 
 1 % wit h d e xa m et
 ( n e ar 
C R) r at e w a s 1 3 % wit h b ort e z o mi b v er s u s 2 % wit h d e x a m et h a s o n e.  I n p ati e nt s w h o h a d 
r e c ei v e d o nl y 1 pri or li n e of tr e at m e nt ( b ort e z o mi b:  1 3 2; d e x a m et h a s o n e:  1 1 9), C R + P R 
w a s  4 5 %  wit h  b ort e z o mi b  v s  2 6 %  wit h  d e x a m et h a s o n e  ( p  =  0. 0 0 3 5).    Wit h  a  m e di a n  8. 3 
m o nt h s of f oll o w u p, o v er all s ur vi v al w a s si g nifi c a ntl y l o n g er ( p = 0. 0 0 1 3) f or p ati e nt s o n t h e 
b ort e z o mi b ar m v er s u s p ati e nt s o n t h e d e x a m et h a s o n e ar m.  T h e pr o b a bilit y of s ur vi v al at 
1 y e ar  w a s  8 0 %  f or  t h e  V E L C A D E  ar m  v er s u s  6 6 %  f or  t h e  d e x a m et h a s o n e  ar m w hi c h 
r e pr e s e nt e d  a  4 1 %  d e cr e a s e d  r el ati v e  ri s k  of  d e at h  i n  t h e  fir st  y e ar  wit h  b ort e z o mi b 


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(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 M34101-039.37  
The updated CR + PR rate was 43% with VELCADE.  The CR + nCR rate was 16% with 
VELCADE.  With a median 22 months of follow-up, overall survival was significantly longer 
for patients on the bortezomib arm versus patients on the dexamethasone arm.  The 
median overall survival was 29.8 months (95% CI:  23.2, not estimable) for the VELCADE 
arm vs 23.7 months (95% CI:  18.7, 29.1) for the dexamethasone arm (hazard ratio = 0.77, 
p = 0.0272).  The probability of survival at 1 year was 80% for the bortezomib arm versus 
67% for the dexamethasone arm (p = 0.0002). 
The safety and efficacy of VELCADE 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.38  The single-arm study was designed to evaluate the response 
rates, duration of response (DOR), TTP, overall survival (OS), and safety of bortezomib 
treatment in patients with relapsed or refractory mantle cell lymphoma. For 141 evaluable 
patients, the response rate was 31% (8% CR/unconfirmed CR [Cru]).  Median time to 
response was 40 days (range 31-204 days).  The median number of cycles administered 
across all patients was 4; in responding patients, the median number of cycles was 8.  The 
median DOR by algorithm was 9.2 months and 13.5 months in patients with CR/CRu.  
Median TTP for both groups was 6.2 months.  With a median follow-up of 13.4 months, 
overall survival had not been reached.  The most commonly reported adverse events (AEs) 
were fatigue, peripheral neuropathy, and gastrointestinal events.  A time-to-event update to 
the PINNACLE study39 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 VELCADE, melphalan, and prednisone in previously 
untreated multiple myeloma patients who were not candidates for stem cell transplant.40  
The study was designed to determine the benefit of adding VELCADE 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 VELCADE 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 


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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 VELCADE 
(VMP) group compared to 34% in the MP group (p = 0.001).  With follow-up of 16.3 months, 
the TTP for the VMP group was 24 months compared to 16.6 months in the MP group (p = 
0.000001) and was associated with a 52% reduced time to progression.  The median DOR 
was 19.9 months in the VMP group and 13.1 months in the MP group.  Overall survival had 
not been reached in either group.  Hematologic toxicity was similar in both groups.  The 
incidence of peripheral sensory neuropathy and gastrointestinal symptoms was higher in 
the VMP group.  The incidence of herpes zoster was 3% in patients in the VMP group who 
received antiviral prophylaxis.  Fifteen percent of patients in the VMP group discontinued 
therapy due to AEs compared to 14% in the MP group. 
The VISTA study update after extended follow-up of 25.9 months,41 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 
VELCADE. 
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).42 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). 
SUBCUTANEOUS ADMINISTRATION  
A randomized Phase 1 pilot study in 24 subjects with multiple myeloma demonstrated that 
both the IV and SC routes of VELCADE administration have similar systemic drug exposure 
and proteasome inhibition. Importantly, SC and IV administration of VELCADE 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 
VELCADE, when administered at 1 mg/mL concentration.  


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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/m2 dose and twice per week schedule in patients with 
relapsed multiple myeloma 26. 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 VELCADE 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 very good partial response (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. 
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, 


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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 VELCADE SC administration is not inferior to VELCADE IV 
administration.26 
1.2.6    Potential Risks of VELCADE  
To date, more than 300,000 patients have been treated with VELCADE in both clinical trials 
investigating its use in hematological malignancies and solid tumors, and in patients who 
were treated with commercially available VELCADE. 
Prescribing physicians and health care practitioners are referred to their locally approved 
product label for VELCADE regarding Indications and Usage, Contraindications, Warnings, 
and Precautions. 
The known anticipated risks of VELCADE therapy are presented in Table 1-2 and Table 
1-3.  These risks are grouped according to the combined frequency observed in an 
integrated analysis of AEs in sponsored clinical studies of single-agent VELCADE dosed at 
1.3 mg/m2 twice weekly on a 21-day schedule, in patients with multiple myeloma and 
mantle cell lymphoma. 


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Table 1-2    
Known Anticipated Risks of VELCADE by MedDRA System Organ Class, 
Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
 
Blood and Lymphatic System Disorders 
Most common 
Thrombocytopenia*, anaemia* 
Very common  
Neutropenia* 
Common  
Lymphopenia, pancytopenia*, leukopenia*, febrile 
neutropenia 
Cardiac Disorders 
Common  
Tachycardia, atrial fibrillation, palpitations, cardiac 
failure congestive* 
Uncommon 
Cardiogenic shock*, atrial flutter, cardiac 
tamponade*±, bradycardia, atrioventricular block 
complete, arrhythmia, cardiac arrest∗, cardiac 
failure, arrhythmia, pericardial effusion, pericarditis, 
pericardial disease±, cardiopulmonary failure± 
Ear and Labyrinth Disorders 
Uncommon 
Deafness, hearing impaired 
Eye Disorders 
Common  
Blurred vision, conjunctivitis, conjunctival 
haemorrhage  
Gastrointestinal Disorders 
Most common 
Constipation, diarrhoea*, nausea, vomiting* 
Very common  
abdominal pain (excluding oral and throat) 
Common  
Dyspepsia, pharyngolaryngeal pain, 
gastroesophageal reflux, abdominal distension, 
gastritis, stomatitis, mouth ulceration, dysphagia, 
gastrointestinal haemorrhage*, lower 
gastrointestinal haemorrhage*± rectal haemorrhage 
Uncommon 
Eructation, gastrointestinal pain, tongue ulceration, 
retching, upper gastrointestinal haemorrhage*, 
haematemesis*, oral mucosal petechiae, ileus 
paralytic*, ileus, odynophagia, enteritis, colitis, 
oesophagitis, enterocolitis, diarrhoea 
haemorrhagic, acute pancreatitis*, intestinal 
obstruction 
General Disorders and Administration Site Conditions 
Most common 
Fatigue, pyrexia 
Very common  
Chills, oedema peripheral, asthenia 
Common  
Neuralgia, lethargy, malaise, chest pain, mucosal 
inflammation* 
Uncommon 
Injection site pain, injection site irritation, injection 
site phlebitis, general physical health deterioration*, 
catheter-related complication 


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Table 1-2    
Known Anticipated Risks of VELCADE by MedDRA System Organ Class, 
Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
 
Hepatobiliary Disorders 
Uncommon 
Hyperbilirubinaemia, hepatitis*± 
 
Immune System Disorders 
Uncommon 
Drug hypersensitivity, angioedema 
 
Infections and Infestations 
Very common  
Upper respiratory tract infection, nasopharyngitis, 
pneumonia*, Herpes zoster* 
Common  
Lower respiratory tract infection*, sinusitis, 
pharyngitis, oral candidiasis, urinary tract infection*, 
sepsis∗, bactaeremia*, cellulitis∗, Herpes simplex, 
bronchitis, gastroenteritis*, infection 
Uncommon 
Septic shock*, catheter-related infection*, skin 
infection*, Herpes zoster disseminated*, lung 
infection∗, infusion site cellulitis, catheter site 
cellulitis, infusion site infection, urosepsis*, 
Aspergillosis*, tinea infection, Herpes zoster 
ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic±, varicella, 
empyema±, fungal oesophagitis± 
 
Injury, Poisoning, and Procedural Complications  
Common 
Fall 
Uncommon 
Subdural haematoma 
 
Investigations 
Common  
Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) 
increased, blood alkaline phosphatase increased, 
liver function test abnormal, blood creatinine 
increased* 
Uncommon 
Gamma-glutamyltransferase (GGT) increased, 
oxygen saturation decreased*, blood albumin 
decreased, ejection fraction decreased* 
 
Metabolism and Nutritional Disorders 
Very common  
Decreased appetite, anorexia, dehydration* 
Common  
Hyperglycaemia, hypoglycaemia, hyponatraemia, 
hypokalaemia, hypercalcaemia* 
 


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Table 1-2    
Known Anticipated Risks of VELCADE by MedDRA System Organ Class, 
Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
 
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 φ 
 
Psychiatric Disorders 
Very common 
Anxiety, insomnia  
Common 
Confusional state  
Uncommon 
Delirium 
 
Renal and Urinary Disorders 
Common 
Renal impairment*, renal failure*, haematuria 
Uncommon 
Micturition disorder 
 
Respiratory, Thoracic, and Mediastinal Disorders 
Very common 
Cough, dyspnoea  
Common 
Epistaxis, dyspnoea exertional, pleural effusion*, 
rhinorrhea, hypoxia*, pulmonary oedema∗ 
Uncommon 
Hemoptysis*, acute respiratory distress syndrome*, 
respiratory failure*, pneumonitis*, lung infiltration, 
pulmonary alveolar haemorrhage*, interstitial lung 
disease*, pulmonary hypertension*, pleurisy, 
pleuritic pain 
 


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Table 1-2    
Known Anticipated Risks of VELCADE by MedDRA System Organ Class, 
Observed Incidence, and Preferred Term 
System Organ Class 
Observed Incidence 
Preferred Term 
 
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® Investigator’s Brochure Edition 17. 
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. 
φ  Effective MedDRA update to version 14.0, the term ‘reversible posterior leukoencephalopathy syndrome’ 
updated to ‘posterior reversible encephalopathy syndrome (PRES)’.  
 


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Table 1-3    
Reports of Adverse Reactions From Postmarketing 
Experience 
System Organ Class  
Preferred Term 
Observed 
Incidencea 
Blood and lymphatic system disorders 
 
 
Disseminated intravascular coagulation  
Rare 
Cardiac Disorders 
 
 
Atrioventricular block complete 
Rare 
 
Cardiac tamponade 
Rare 
Ear and labyrinth disorders 
 
 
Deafness bilateral 
Rare 
Eye Disorders 
 
 
Ophthalmic herpes 
Rare 
              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 


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Table 1-3    
Reports of Adverse Reactions From Postmarketing 
Experience 
System Organ Class  
Preferred Term 
Observed 
Incidencea 
 
Lung infiltration 
Rare 
 
Pneumonitis 
Rare 
 
Pulmonary hypertension 
Rare 
Skin and subcutaneous system disorders 
 
 
Acute febrile neutrophilic dermatosis 
Unknown 
 
Toxic epidermal necrolysis 
Unknown 
Source:  VELCADE® Investigator’s Brochure Edition 17. 
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 VELCADE 
include hepatic failure and QT prolongation.  Fatal outcomes have been reported. 
Women of childbearing potential should avoid becoming pregnant while being treated with 
VELCADE.  Genotoxicity testing has shown that VELCADE is negative in the in vitro Ames 
assay and in the in vivo micronucleus assay, but it is a clastogen in the in vitro 
chromosomal aberration assay. 
Additional details on the potential risks of VELCADE may be found in the 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 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 


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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 white blood cells (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 
reported. 26 
1.3  Pegylated liposomal doxorubicin (Doxil) 
1.3.1   
Scientific Background 
Doxorubicin HCl liposome injection is a cytotoxic anthracycline antibiotic isolated from 
Streptomyces peucetius var. caesius. The mechanism of action of doxorubicin HCl is 
thought to be related to its ability to bind to DNA and inhibit nucleic acid synthesis. Cell 


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structure studies have demonstrated rapid cell penetration and perinuclear chromatin 
binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of 
mutagenesis and chromosomal aberrations (Doxil® Product Information Booklet 2005). 
Greater than 90% of the drug (doxorubicin) is encapsulated in STEALTH® liposomes, 
microscopic vesicles composed of phospholipid bilayer that are capable of encapsulating 
active drugs. It is hypothesized that because of their small size (ca. 100 nm) and 
persistence in the circulation, the pegylated liposomes are able to penetrate the altered and 
often compromised vasculature of tumors. This hypothesis is supported by studies using 
colloidal gold-containing STEALTH® liposomes, which can be visualized microscopically. 
Evidence of penetration of STEALTH® liposomes from blood vessels and their entry and 
accumulation in tumors has been seen in mice with C-26 colon carcinoma tumors and in 
transgenic mice with Kaposi's sarcoma-like lesions. Once the STEALTH® liposomes 
distribute to the tissue compartment, the encapsulated doxorubicin HCl becomes available. 
The exact mechanism of release is not understood (Doxil® Product Information Booklet 
2005). 
 
Pegylated liposomal doxorubicin is a common treatment option, approved for patients with 
metastatic recurrent ovarian carcinoma who are refractory to paclitaxel and platinum-based 
chemotherapy. Although doxorubicin has been associated with poor response in recurrent 
ovarian cancer, pegylated liposomal doxorubicin has demonstrated efficacy in the treatment 
of recurrent/relapsed ovarian cancer in several clinical trials. Long-term follow up has 
shown that pegylated liposomal doxorubicin significantly prolongs survival compared with 
topotecan for patients with platinum sensitive recurrent ovarian carcinoma. Median overall 
survival was 107.9 weeks for platinum sensitive patients treated with pegylated liposomal 
doxorubicin compared to 70.1 weeks for those treated with topotecan43.  For patients with 
platinum refractory disease, no statistically significant difference in survival was observed 
between the two groups. Median overall survival was 35.6 weeks for platinum refractory 
patients treated with pegylated liposomal doxorubicin compared to 41.3 weeks for those 
treated with topotecan.44  
 
1.3.2    
Nonclinical Pharmacology 
Please see package insert (Appendix 8.8) 
1.3.3   
Nonclinical Toxicity 
Please see package insert (Appendix 8.8) 


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1.3.4   
Clinical Pharmacokinetics and Pharmacodynamics 
According to the most recent label for pegylated liposomal doxorubicin (Doxil® Product 
Information Booklet 2005), linear pharmacokinetics were observed in 23 male Kaposi’s after 
administration, with a relatively short first phase (approximately 5 hrs) and a prolonged 
second phase (approximately 55 hrs) that accounted for the majority of the area under the 
curve (AUC). At 50mg/m2, the pharmacokinetics are reported to be nonlinear. At this dose 
the elimination halflife is expected to be longer and the clearance lower (compared to 20 
mg/m2). The exposure (AUC) is expected to be more than proportional at a 50 mg/m2 dose 
when compared with the lower doses. In contrast to the pharmacokinetics of doxorubicin, 
which displays a large volume of distribution, ranging from 700 to 1100 L/m2, the small 
steady state volume of distribution of pegylated liposomal doxorubicin shows that it is 
confined mostly to the vascular fluid volume. Plasma protein binding has not been 
determined for pegylated liposomal doxorubicin but is approximately 70% for doxorubicin. 
Doxorubicinol, the major metabolite of doxorubicin, was detected at very low levels (range: 
0.8 to 26.2 ng/mL) in the plasma of patients who received 10 or 20 mg/m2 pegylated 
liposomal doxorubicin. Plasma clearance was slow, with a mean clearance value of 0.041 
L/h/m2 at a dose of 20 mg/m2. This is in contrast to doxorubicin, which displays a clearance 
value from 24 to 35L/h/m2. Because of its slower clearance, the AUC of pegylated 
liposomal doxorubicin, primarily representing the circulating liposome-encapsulated 
doxorubicin, is approximately two to three times larger than the AUC for a similar dose of 
conventional doxorubicin HCl. Pharmacokinetics have not been separately evaluated in 
women, different ethnic groups or in individuals with renal or hepatic insufficiency. Drug-
drug interactions between pegylated liposomal doxorubicin and other drugs, including 
antiviral agents, have not been evaluated. 
1.3.5   
Clinical Experience 
Doxil has a number of clinical indications approved by the FDA. Its use in recurrent 
epithelial ovarian cancer patients who had failed platinum and taxane based therapy was 
established early on. A Phase II study that included the use of Doxil was performed in thirty-
five consecutive patients with progressive ovarian cancer after either cisplatin or carboplatin 
and paclitaxel, or at least one platinum-based and one paclitaxel-based regimen.45 Patients 
received intravenous (IV) liposomal doxorubicin 50 mg/m2 every 3 weeks. Nine clinical 
responses (one complete response, eight partial responses) were observed (25.7%), The 
median progression-free survival was 5.7 months with an overall survival of 1.5 to 24+ 
months (median, 11 months). The most common toxicity that was associated with Doxil was 
the hand-foot syndrome (palmar-plantar erythrodysesthesia) seen in up to 20% of the 
patients in the above study. When the dose was decreased from 50mg/m2 to 40mg/m2, the 
anti-tumor effect was preserved with a significant improvement in the toxicity profile. 


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Doxil was then tested against Topotecan in a phase III trial in patients with relapsed or 
platinum refractory epithelial ovarian cancer. In this study, 474 patients with measurable 
and assessable disease were randomized to receive either PLD 50 mg/m2 as a 1-hour 
infusion every 4 weeks or topotecan 1.5 mg/m2/d for 5 consecutive days every 3 weeks.46 
The overall response rates for Doxil and Topotecan were 19.7% and 17.0%, respectively (P 
=.390). Median overall survival times were 60 weeks for PLD and 56.7 weeks for topotecan.  
For overall survival, Doxil was significantly superior to topotecan (P =.008), with a median 
of 108 weeks versus 71.1 weeks. Given the durability of responses as well as minimal 
toxicities associated with the drug, Doxil became an attractive treatment choice in relapsed 
or platinum refractory epithelial ovarian cancer.   
 
The use of Doxil in metastatic breast cancer was established when non-inferiority of this 
drug to Doxorubicin was demonstrated. When two were compared in over 500 patients with 
metastatic breast cancer and normal cardiac function, the overall survival in the two groups 
were similar, but toxicities significantly lower in the Doxil group.47 Overall survival was 21 
and 22 months for Doxil and doxorubicin, respectively; HR=0.94; 95%CI 0.74-1.19. 
Alopecia (overall, 66% versus 20%; pronounced, 54% versus 7%), nausea (53% versus 
37%), vomiting (31% versus 19%) and neutropenia (10% versus 4%) were more often 
associated with doxorubicin than Doxil. Palmar-plantar erythrodysesthesia (48% versus 
2%), stomatitis (22% versus 15%) and mucositis (23% versus 13%) were more often 
associated with Doxil than doxorubicin.  
 
Doxil is considered to be the accepted first-line therapy in AIDS-related Kaposi’s sarcoma. 
Two Phase III trials compared single agent Doxil at a dose of 20mg/m2 to a multi-agent 
chemotherapy regimen that included bleomycin and vincristine.48,49Results noted a superior 
response rate in the patients in the Doxil group with fewer toxicities. 
 
The combination of Doxil and Velcade has been studied in and is currently a FDA-approved  
treatment option for relapsed multiple myeloma. The DOXIL-MMY-3001 trial was a 
randomized phase III trial that studied either Velcade 1.3 mg/m2 on days 1, 4, 8, and 11 of 
an every 21-days cycle, or the same bortezomib regimen with Doxil 30 mg/m2 on day 4 in 
646 patients.50 Median time to progression improved from 6.5 months for bortezomib to 9.3 
months with the Doxil + bortezomib combination (P = 0.000004; hazard ratio, 1.82 
[monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for 
doxil and bortezomib was 76% compared with 65% for bortezomib alone (P = 0.03). The 
complete plus partial response rate was 41% for bortezomib and 44% for Doxil + 
bortezomib, a difference that was not statistically significant. Median duration of response 
was increased from 7.0 to 10.2 months (P = 0.0008) with Doxil + bortezomib. Grade 3/4 


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adverse events though were more frequent in the combination group (80% v 64%). An 
increased incidence of grade 3/4 neutropenia, thrombocytopenia, asthenia, fatigue, 
diarrhea, and hand-foot syndrome was seen in the combination group. Notably, any grade 
hand-foot syndrome occurred in 16% of subjects with Doxil + bortezomib with 5% of 
subjects experiencing grade 3 and 0% grade 4. Grade 3/4 peripheral neuropathy was seen 
in 4% of subjects. 
  
 1.4 
Decitabine 
 
1.4.1 Scientific Background 
 
Decitabine (5-aza-2’-deoxycitidine), an analogue of the natural nucleoside 2’-deoxycytidine, 
is a member of the hypomethylator or DNA methyltransferase inhibitor class. Decitabine is 
believed to exert its antineoplastic effects after phosphorylation and direct incorporation into 
DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular 
differentiation or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved 
at concentrations that do not cause major suppression of DNA synthesis. Decitabine-
induced hypomethylation in neoplastic cells may restore normal function to genes that are 
critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the 
cytotoxicity of decitabine may also be attributed to the formation of covalent adducts 
between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating 
cells are relatively insensitive to decitabine. 
 
Decitabine is indicated for treatment of patients with myelodysplastic syndromes (MDS) 
including previously treated and untreated, de novo and secondary MDS of all French-
American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, 
refractory anemia with excess blasts, refractory anemia with excess blasts in 
transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, 
and high-risk International Prognostic Scoring System groups. Decitabine also has 
significant activity in AML as described in Section 1.1.53-54,59-62 For more details, please refer 
to the Decitabine package insert (Appendix 8.10). 
 
1.4.2 Nonclinical Pharmacology 
 
Please refer to the Decitabine package insert (Appendix 8.10). 
 
1.4.3 Nonclinical Toxicity 
 
Please refer to the Decitabine package insert (Appendix 8.10). 


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Carcinogenicity studies with decitabine have not been conducted. 
 
The mutagenic potential of decitabine was tested in several in vitro and in vivo systems. 
Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations 
were produced in an Escherichia coli lac-I transgene in colonic DNA of decitabine treated 
mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies. 
 
The effect of decitabine on postnatal development and reproductive capacity was evaluated 
in mice administered a single 3 mg/m2 IP injection (approximately 7% the recommended 
daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in 
utero to decitabine were significantly reduced relative to controls at all postnatal time points. 
No consistent effect on fertility was seen when female mice exposed in utero were mated to 
untreated males. Untreated females mated to males exposed in utero showed decreased 
fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). In male mice 
given IP injections of 0.15, 0.3 or 0.45 mg/m2 decitabine (approximately 0.3% to 1% the 
recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, 
body weight gain or hematological measures (hemoglobin and WBC counts). Testes 
weights were reduced, abnormal histology was observed and significant decreases in 
sperm number were found at doses ≥0.3 mg/m2. In females mated to males dosed with 
≥0.3 mg/m2 decitabine, pregnancy rate was reduced and preimplantation loss was 
significantly increased. 
 
1.4.4 Clinical Pharmacokinetics and Pharmacodynamics 
 
Please refer to the Decitabine package insert (Appendix 8.10). 
 
Decitabine has been shown to induce hypomethylation both in vitro and in vivo. However, 
there have been no studies of decitabine-induced hypomethylation and pharmacokinetic 
parameters. 
 
Pharmacokinetic parameters were evaluated in patients. Eleven patients received 20 
mg/m2 infused over 1 hour intravenously (treatment Option 2). Fourteen patients received 
15 mg/m2 infused over 3 hours (treatment Option 1). Plasma concentration-time profiles 
after discontinuation of infusion showed a bi-exponential decline. The CL of decitabine was 
higher following treatment Option 2. Upon repeat doses there was no systemic 
accumulation of decitabine or any changes in PK parameters. Population PK analysis 
(N=35) showed that the cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower 
than the cumulative AUC per cycle following treatment Option 1. 


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The exact route of elimination and metabolic fate of decitabine is not known in humans. 
One of the pathways of elimination of decitabine appears to be deamination by cytidine 
deaminase found principally in the liver but also in granulocytes, intestinal epithelium and 
whole blood. 
 
1.4.5 Clinical Experience 
 
Please refer to the Decitabine package insert (Appendix 8.10). 
 
A randomized open-label, multicenter, controlled trial evaluated 170 adult patients with 
myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification 
criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and 
Intermediate-1 prognostic scores. Eighty-nine patients were randomized to decitabine 
therapy plus supportive care (only 83 received decitabine), and 81 to Supportive Care (SC) 
alone. Patients with Acute Myeloid Leukemia (AML) were not intended to be included. Of 
the 170 patients included in the study, independent review (adjudicated diagnosis) found 
that 12 patients (9 in the decitabine arm and 3 in the SC arm) had the diagnosis of AML at 
baseline. Baseline demographics and other patient characteristics in the Intent-to-Treat 
(ITT) population were similar between the 2 groups. 
 
Patients randomized to the decitabine arm received decitabine intravenously infused at a 
dose of 15 mg/m2 over a 3-hour period, every 8 hours, for 3 consecutive days. This cycle 
was repeated every 6 weeks, depending on the patient’s clinical response and toxicity. 
Supportive care consisted of blood and blood product transfusions, prophylactic antibiotics, 
and hematopoietic growth factors. The study endpoints were overall response rate 
(complete response + partial response) and time to AML or death. Responses were 
classified using the MDS International Working Group (IWG) criteria; patients were required 
to be RBC and platelet transfusion independent during the time of response. 
 
The overall response rate (CR+PR) in the ITT population was 17% in decitabine-treated 
patients and 0% in the SC group (p<0.001). The overall response rate was 21% (12/56) in 
decitabine -treated patients considered evaluable for response (i.e., those patients with 
pathologically confirmed MDS at baseline who received at least 2 cycles of treatment). The 
median duration of response (range) for patients who responded to decitabine was 288 
days (116-388) and median time to response (range) was 93 days (55-272). All but one of 
the decitabine -treated patients who responded did so by the fourth cycle. Benefit was seen 
in an additional 13% of decitabine -treated patients who had hematologic improvement, 
defined as a response less than PR lasting at least 8 weeks, compared to 7% of SC 


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patients. Decitabine treatment did not significantly delay the median time to AML or death 
versus supportive care. All patients with a CR or PR were RBC and platelet transfusion 
independent in the absence of growth factors. Responses occurred in patients with an 
adjudicated baseline diagnosis of AML. 
 
Three open-label, single-arm, multicenter studies were conducted to evaluate the safety 
and efficacy of decitabine in MDS patients with any of the FAB subtypes. In one study 
conducted in North America, 99 patients with IPSS Intermediate-1, Intermediate-2, or high 
risk prognostic scores received decitabine by intravenous infusion at a dose of 20 mg/m2 IV 
over 1-hour daily, on days 1-5 of week 1 every 4 weeks (1 cycle). The results were 
consistent with the results of the controlled trial. 
 
Several studies have evaluated the activity and safety of decitabine in AML, using a variety 
of dosing schedules. These studies are described in Section 1.1.53-54,59-62 In the Cashen et 
al. and Kantarjian et al. studies, the overall response rate was 25% and 17.8% respective 
using a 5-day dosing schedule at 20mg/m2 IV.53-54 In the Blum et al., Bhatnagar et al. and 
Ritchie et al. studies, the overall response rate varied from 40-64% in the untreated setting 
and 16% in the relapsed/refractory setting.59-62 Toxicities were similar in these studies and 
primarily included myelosuppresion, febrile neutropenia and infections, which are typical of 
this patient and disease population.  
 
1.4.6 Potential Risks of Decitabine 
 
For complete information on adverse reactions associated with Decitabine, please refer to 
the package insert section 6 and section 6 Tables 1 and 2 (Appendix 8.10). 
 
Most Commonly Occurring Adverse Reactions: neutropenia, thrombocytopenia, anemia, 
fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia. 
 
Adverse Reactions Most Frequently (≥1%) Resulting in Clinical Intervention in the Phase 3 
Trials in the DECITABINE Arm: 
• Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium 
complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial 
hemorrhage, abnormal liver function tests. 
• Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, 
febrile neutropenia. 
• Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, 
depression, pharyngitis. 
 


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Discussion of Clinically Important Adverse Reactions 
In the controlled trial using DECITABINE dosed at 15 mg/m2, administered by continuous 
intravenous infusion over 3 hours repeated every 8 hours for 3 days, the highest incidence 
of Grade 3 or Grade 4 adverse events in the DECITABINE arm were neutropenia (87%), 
thrombocytopenia (85%), febrile neutropenia (23%) and leukopenia (22%). Bone marrow 
suppression was the most frequent cause of dose reduction, delay and discontinuation. Six 
patients had fatal events associated with their underlying disease and myelosuppression 
(anemia, neutropenia, and thrombocytopenia) that were considered at least possibly related 
to drug treatment. Of the 83 DECITABINE-treated patients, 8 permanently discontinued 
therapy for adverse events; compared to 1 of 81 patients in the supportive care arm. 
 
In the single-arm study (N=99) when DECITABINE was dosed at 20 mg/m2 intravenous, 
infused over one hour daily for 5 consecutive days, the highest incidence of Grade 3 or 
Grade 4 adverse events were neutropenia (37%), thrombocytopenia (24%) and anemia 
(22%). Seventy-eight percent of patients had dose delays, the median duration of this delay 
was 7 days and the largest percentage of delays was due to hematologic toxicities. 
Hematologic toxicities and infections were the most frequent causes of dose delays and 
discontinuation. Eight patients had fatal events due to infection and/or bleeding (seven of 
which occurred in the clinical setting of myelosuppression) that were considered at least 
possibly related to drug treatment. Nineteen of 99 patients permanently discontinued 
therapy for adverse events. No overall difference in safety was detected between patients 
>65 years of age and younger patients in these myelodysplasia trials. No significant gender 
differences in safety or efficacy were detected. Patients with renal or hepatic dysfunction 
were not studied. Insufficient numbers of non-white patients were available to draw 
conclusions in these clinical trials. 
 
Serious Adverse Events that occurred in patients receiving DECITABINE regardless of 
causality, include: 
• Blood and Lymphatic System Disorders: myelosuppression, splenomegaly. 
• Cardiac Disorders: myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial 
fibrillation, supraventricular tachycardia. 
• Gastrointestinal Disorders: gingival pain, upper gastrointestinal hemorrhage. 
• General Disorders and Administrative Site Conditions: chest pain, catheter site 
hemorrhage. 
• Hepatobiliary Disorders: cholecystitis. 
• Infections and Infestations: fungal infection, sepsis, bronchopulmonary aspergillosis, 
peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, 
Mycobacterium avium complex infection. 
• Injury, Poisoning and Procedural Complications: post procedural pain, post procedural 


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hemorrhage. 
• Nervous System Disorders: intracranial hemorrhage. 
• Psychiatric Disorders: mental status changes. 
• Renal and Urinary Disorders: renal failure, urethral hemorrhage. 
• Respiratory, Thoracic and Mediastinal Disorders: hemoptysis, lung infiltration, pulmonary 
embolism, respiratory arrest, pulmonary mass. 
• Allergic Reaction: Hypersensitivity (anaphylactic reaction) to DECITABINE has been 
reported in a Phase 2 trial. 
 
Post-marketing Experience 
The following adverse reactions have been identified during postapproval use of 
DECITABINE. Because these reactions are reported voluntarily from a population of 
uncertain size, it is not always possible to reliably estimate their frequency or establish a 
causal relationship to drug exposure. Cases of Sweet’s Syndrome (acute febrile 
neutrophilic dermatosis) have been reported. 
 
1.5    Study Rationale and Selection of Drug Doses  
 
Acute myeloid leukemia remains largely incurable despite advances that have been made 
in recent years into increasing the complete response (CR) rates. In elderly patients (over 
the age of 60), CR rates are lower, 40 to 50%, and long term disease-free and overall 
survival is less than 10% (Dohner et al).1 The therapeutic options for relapsed/refractory 
AML are significantly limited. Bortezomib has shown promising activity in patients with 
advanced hematologic malignancies, including those with leukemia and non-Hodgkin’s 
lymphoma.  Pre-clinical studies have shown that proteasome inhibition promotes apoptosis 
of tumor cells in part through stabilization of the negative regulator of nuclear factor kappa 
B (NF-κB).  Several in-vitro studies have also shown bortezomib to induce apoptosis in 
human AML cells.  In addition a recent phase I study that utilized bortezomib in combination 
with standard induction therapy patients with relapsed/refractory AML was shown to 
produce high response rates with minimal additional toxicity.51 In this study there was no 
MTD established for bortezomib with the highest dose being 1.5mg/m2 given on days 1,4, 8 
and 11. Anthracyclines, in part, exert anti-tumor activity by inducing an NF-κB driven, anti-
apoptotic process. Laboratory evidence has suggested that activity of the transcription 
factor NF-κB promotes anthracycline resistance.   This particular resistance can be 
overcome when a proteosome inhibitor is given in conjunction with the anthracycline.   
Orlowski and colleagues performed a phase I study of bortezomib combined with pegylated 
liposomal doxorubicin (Doxil) in patients with advanced hematologic malignancies resulting 
in a number of patients (with MM, T-cell NHL, B-cell NHL) achieving significant responses.  
This was confirmed in a phase III trial in patients with relapsed Myeloma and the 


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combination of Velcade and Doxil is FDA approved for the treatment of relapsed myeloma.  
Given the available data suggesting efficacy of bortezomib in combination with doxil in 
patients with relapsed MM, chronic lymphocytic leukemia (CLL), and NHL as well as the 
known sensitivity of AML to anthracylines and in vitro data demonstrating the sensitivity of 
multiply resistant AML cells to bortezomib, we proposed the use of this combination in 
patients with relapsed/refractory AML or elderly patients that are not candidates for 
standard induction therapy.52 We enrolled 15 patients who were evaluable. Toxicity was 
manageable with 13% of patients experiencing grade 3 neurotoxicity. Three partial 
responses were seen and there were reductions in blast counts in 79% of patients. The 
duration of response was short and the maximum number of completed cycles was two. 
 
The hypomethylating agents (HMA), including decitabine, have significant activity in AML 
and have been shown to work primarily through inhibition of DNA methyltransferase 
enzymes and NF-κB.53-58 Recently, a 10-day dosing schedule of decitabine (at 20mg/m2 IV 
days 1-10 on a 28-day cycle) for AML has demonstrated significant activity, with CR rates 
of 40-64% in untreated older patients and 16% in relapsed/refractory patients.59-61 The 
regimen is well-tolerated with febrile neutropenia, infections and myelosuppression most 
common. The 10-day decitabine regimen was combined with IV bortezomib in a phase I 
study in relapsed/refractory AML or untreated older patients.62 The bortezomib dose was 
escalated to 1.3mg/m2 on days 5, 8, 12 and 15 without dose-limiting toxicities. Toxicities 
were similar to the 10-day decitabine studies, and grade 3 neurotoxicity related to 
bortezomib was seen in 3 of 19 patients (all three events were after induction). CR was 
achieved in 50% of untreated and 22% of relapsed/refractory patients. These studies 
continued decitabine with or without bortezomib until disease progression or unacceptable 
toxicity.53-54,59-62 Based on these studies, there is an ongoing clinical trial using the 
combination of 10-day decitabine and bortezomib (NCT01420926). In NCT01420926, three 
of the bortezomib doses are being administered concurrently with the 10-days of decitabine 
(decitabine days 2-11 and bortezomib days 1, 4, 8 and 11). 
 
Given that we have shown the combination of SQ bortezomib and pegylated liposomal 
doxorubicin is safe and has activity in relapsed/refractory AML and the combination of 
decitabine and IV bortezomib is safe and has activity in relapsed/refractory AML, we 
propose testing the combination of decitabine, SQ bortezomib and pegylated liposomal 
doxorubicin in patients with relapsed/refractory AML or older untreated patients unfit for or 
who refuse induction chemotherapy. We will use dosing schema established as safe and 
effective from the prior studies, including the 10-day decitabine dosing and bortezomib at 
1.3mg/m2 and administration of post-induction therapy. One difference from the prior 
published regimen of 10-day decitabine and IV bortezomib is that we will give the 
bortezomib SQ, which is associated with decreased toxicity. Since the combination of all 


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three drugs is untested, however, we will assess for DLTs at our proposed starting dose 
levels using a 6-9 patient safety-lead in stage. Given that the first two subjects dosed on the 
dosing schedule per Amendment 9 both experienced DLTs of peripheral neuropathy, we 
have modified the dosing schedule in the current Amendment 10 and will start a new 6-9 
patient safety lead-in stage. We will adjust the bortezomib dosing per the Blum et al 
regimen (62) during induction and move PLD later in the cycle to day 12. Our hypothesis is 
that there was synergistic toxicity between the three agents when given concurrently and 
this schedule will administer the PLD after completion of the decitabine and some of the 
bortezomib doses. The new dosing schedule is hypothesized to remain mechanistically 
relevant, given our hypothesis that NF-kB signaling can mediate anthracycline resistance 
and bortezomib inhibits NF-kB signaling. To lessen risk of neuropathy during post-induction 
courses, we are eliminating the day 15 and day 22 bortezomib doses and moving PLD later 
in the cycles to day 12.  
 
2.    
STUDY OBJECTIVES 
2.1    Primary Objectives 
The primary objectives of this study are to: 
• 
Assess response rate and progression free survival (PFS) 
2.2    Secondary Objectives 
The secondary objectives of this study are to: 
• 
Assess overall survival and toxicity 
 
3.    
INVESTIGATIONAL PLAN 
This is an investigator-initiated study.  The principal investigator, Joseph Tuscano, MD, 
otherwise known as the sponsor-investigator, is considered the study sponsor. 
3.1    Overall Design and Plan of the Study  
This is a Phase II, open label study of the combination of decitabine, bortezomib and 
pegylated liposomal doxorubicin for the treatment of patients with relapsed/refractory acute 
myeloid leukemia (AML) or untreated patients ineligible for standard induction therapy. A 
safety lead-in cohort will test the combination of decitabine, bortezomib and pegylated 
liposomal doxorubicin in the first 6-9 patients.  
 


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Treatment Regimen: 
Induction: 
Decitabine 20mg/m2 (IV) days 1-10 
Bortezomib: 1.3mg/m2 (SQ) days 5, 8, 12, and 15  
Pegylated liposomal doxorubicin: 40mg/m2 (IV) day 12 
Cycle repeats every 28 days 
 
Patients will receive a minimum of 1 cycles and a maximum of 4 cycles of induction. If there 
is no response or progression after two cycles of induction, they will be taken off the study. 
Patients with persistent AML (>5% blasts) in the bone marrow will continue to receive 
induction cycles up to a maximum of 4 cycles. Patients achieving a blast count of less than 
5% after any course of induction will proceed to the post-induction regimen. Dose 
reductions will be permitted as described in Section 3.3.3. Subsequent cycles of induction 
may be delayed at investigator discretion up to 14 days or to allow for resolution of non-
hematologic toxicities to grade 2 or better. There are no hematologic parameters required 
for dosing during the induction phase, since subjects have active AML and blood count 
recovery is not expected. Please refer to the study calendar in Appendix 8.1 for further 
study treatment and assessment details. 
 
Post-Induction: 
Decitabine 20mg/m2 (IV) days 1-5 
Bortezomib: 1.3mg/m2 (SQ) days 1 and 8 
Pegylated liposomal doxorubicin: 40mg/m2 (IV) day 12  
Cycle repeats every 28 days 
 
Patients will receive continued cycles of post-induction therapy until progression, 
intolerance, transplant, withdrawal of informed consent for a maximum of 12 cycles 
(induction cycles are counted towards this total). Dose reductions of decitabine, bortezomib 
and pegylated liposomal doxorubicin are permitted and summarized in Section 3.3.3. 
Additionally, pegylated liposomal doxorubicin will be discontinued once a patient reaches a 
lifetime cumulative doxorubicin dose of 550mg/m2 (prior non-doxorubicin anthracycline 
dose will be included in this calculation, using published conversion factors). Following a 5-
day course of decitabine, subjects without evidence of AML (defined as no minimal residual 
disease by flow cytometry, cytogenetics or molecular markers) but who had grade 4 
neutropenia (<500/µL) of at least a 14-day duration will receive a dose reduction of 
decitabine to 4 days with the next cycle. A second dose reduction of decitabine to 3 days 
per cycle is permitted if grade 4 neutropenia of at least a 14-day duration occurs again. 
Patients with residual AML (defined as presence of minimal residual disease by flow 
cytometry, cytogenetics or molecular markers), however, will continue to receive 5 days of 


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decitabine per cycle. The first and subsequent cycles of post-induction therapy may be 
delayed at investigator discretion up to 14 days or to allow for resolution of non-hematologic 
toxicities to grade 2 or better and to allow neutrophils to recover to greater than 1000/µL 
and platelets to greater than 100,000/µL in patients with CR. For patients in CRi or with 
persistent AML, post-induction therapy may proceed without specific hematologic 
parameters. Use of hematologic growth factors is permitted for patients in CR/CRi. Please 
refer to the study calendar in Appendix 8.1 for further study treatment and assessment 
details. 
 
Rules for the safety lead-in: the above intended induction dose of decitabine, bortezomib 
and pegylated liposomal doxorubicin will be tested in the first 6 patients. If 0-1 dose limiting 
toxicities (DLTs) are observed then the study will continue to accrue as per the Simon’s 
two-stage design (refer to Section 5.2 – these safety lead-in patients will be included in the 
efficacy analysis). If 2 or more DLTs are observed in the first 6 patients, then 3 additional 
subjects will be assessed for DLTs. If 3 or more of the 9 subjects experience DLTs, 
enrollment will be halted and a different schedule or dose considered. The two subjects 
experiencing DLTs at the dosing schedule per Amendment 9 will not be included in this new 
safety lead-in cohort, but will be included in the response assessment as described in 
Section 5.2. For the safety lead-in, if patients do not experience a DLT during cycle 1 but 
miss more than 20% of the total planned treatment doses for the cycle, they will be 
replaced.  
 
Definition of DLT: National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Effects (CTCAE) version 4.03 will be used. Toxicities will be considered related to 
the study drug unless there is a clear, well-documented, alternative explanation for the 
adverse effect.  
 
DLT assessments will be based on treatment-related adverse events (AEs) in the first cycle 
(C1D1-C2D1 pre-dose). All patients who are not evaluable for toxicity will be replaced. 
Subjects will receive cycle 1 therapy regardless of neutropenia, anemia, or 
thrombocytopenia. RBC and platelet transfusion support is allowed during this time. 
Filgrastim will not be permitted during cycle 1, unless indicated for the treatment of febrile 
neutropenia. Antimicrobial prophylaxis will also be allowed. Dose limiting toxicity (DLT) in a 
given patient is defined as:  
 
Any Grade 5 toxicity related to study treatment. 
 
Hematologic: 
Due to the nature of this disease, hematologic AEs will not be considering DLTs; however, 


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prolonged pancytopenia in the presence of a hypocellular bone marrow (i.e. cellularity 5% 
or less without evidence of AML) that lasts greater or equal to two weeks after the end of 
cycle 1 will be considered dose-limiting myelosuppression. 
 
Non-Hematologic: 
 Any Grade 3 or 4 non-hematologic event (per NCI CTCAE, v4.03) that is considered 
related to study treatment in the opinion of the investigator with the following exceptions: 
- Grade 3 infection or febrile neutropenia is not a DLT, however an infection with life-
threatening consequences or requiring urgent intervention (Grade 4) will be considered a 
DLT if it is determined to be study drug related (e.g. in a subject starting treatment with a 
normal neutrophil count).  
Grade 3 fatigue will not be considered a DLT. 
Grade 3 nausea, vomiting or diarrhea persisting greater than or equal to 7 days or Grade 4 
nausea, vomiting or diarrhea despite maximal antiemetic/antidiarrheal therapy will be 
considered a DLT. 
Grade 3 AST or ALT elevation persisting for less than or equal to 7 days will not be 
considered a DLT. Grade 4 AST or ALT elevation lasting for any duration of time will be 
considered a DLT. 
Grade 3 rash persisting for less than or equal to 7 days with or without steroids, unless it is 
a serious form of rash such as Toxic Epidermal Necrolysis, Steven’s Johnson Syndrome or 
other desquamating rash or associated with anaphylaxis, will not be considered a DLT. 
 
3.2 Selection of Patients 
The total number of patients to be enrolled in this study is 29. Fifteen subjects were enrolled 
prior to amendment 7, and up to 14 additional subjects will be enrolled per amendment 7 
(detailed in Section 5.2). 
 
3.2.1    
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
• 
Voluntary written informed consent before performance of any study-related 
procedure not part of normal medical care, with the understanding that consent may 
be withdrawn by the subject at any time without prejudice to future medical care. 
• 
Female patients who:  
o Are postmenopausal for at least 1 year before the Screening visit, OR 
o Are surgically sterile OR  


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o If they are of childbearing potential, agree to practice 2 effective methods of 
contraception at the same time from the time of signing the informed consent  
through 30 days after the last dose of study treatment, OR agree to 
completely abstain from heterosexual intercourse. 
• 
Male patients, even if surgically sterilized (ie, status postvasectomy), who: 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. 
• 
Adults (age 18 to 90) with acute myeloid leukemia (AML), excluding the M3 subtype 
(acute promyelocytic leukemia), that are not likely to respond to conventional 
therapy, including:  
- Relapsed or refractory AML after one to four prior induction regimens (not 
counting consolidation therapies while in CR, not counting autologous 
transplant while in CR, and not counting prior low-intensity or investigational 
therapy)  
 
- Newly diagnosed AML patient’s age not fit for standard therapy   
 
• 
Bone marrow and peripheral blood studies must be available for confirmation of 
diagnosis. Cytogenetics, flow cytometry, and molecular studies (such as Flt-3 
status) will be obtained as per standard practice 
• 
Performance status of 60% or greater by the Karnofsky scale 
• 
A minimum of 2 weeks (or five half-lives) must have elapsed since the completion of 
prior anti-AML chemotherapy. Hydroxyurea for control of blasts is not counted as 
chemotherapy, and may be given prior to and during cycle 1 of induction to control 
the white blood cell count. 
• 
Patients may have had autologous transplant. They must be at least 100 days post 
transplant, and have had recovery of their counts with ANC >1000 and platelets 
greater than 100K at some point post-transplant, and be without active 
cytomegalovirus (CMV) or fungal disease 
• 
There are no minimum hematological parameter requirements prior to the first two 
cycles, as patients with AML and MDS are understood to have low ANC and platelet 
counts when the disease is active. 
• 
Patients must have a serum bilirubin ≤1.5 mg/dl, SGOT and SGPT ≤3 times the 
institutional upper limits of normal (unless due to Gilbert’s syndrome). 


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3.2.2    
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
• 
There is no specific platelet and absolute neutrophil count that will exclude patients 
from this study given the natural history of AML.  
• 
Patient has ≥ Grade 2 peripheral neuropathy  
• 
Patient had myocardial infarction within 6 months prior to enrollment or has New 
York Heart Association (NYHA) Class III or IV heart failure (see Appendix 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 must be 
documented by the investigator as not medically relevant. An LVEF must be > 50. 
• 
Patient has hypersensitivity to VELCADE, boron, or mannitol. 
• 
Female subject is pregnant or lactating.  Confirmation that the subject is not 
pregnant must be established by a negative serum β-human chorionic gonadotropin 
(β-hCG) pregnancy test result obtained during screening.  Pregnancy testing is not 
required for postmenopausal or surgically sterilized women. 
• 
Female patients who are lactating or have a positive serum pregnancy test during 
the screening period, or a positive urine pregnancy test on Day 1 before first dose of 
study drug, if applicable. 
• 
Serious medical or psychiatric illness likely to interfere with participation in this 
clinical study. 
• 
Diagnosed or treated for another malignancy within 3 years of enrollment, with the 
exception of complete resection of basal cell carcinoma or squamous cell carcinoma 
of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. 
• 
Participation in clinical trials with other investigational agents not included in this 
trial, within 14 days of the start of this trial and throughout the duration of this trial. 
• 
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. 


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• 
Patients with active/uncontrolled CNS leukemia  
 
• 
Patients eligible, at the time of starting treatment, for curative therapeutic 
approaches (such as allogeneic transplant) are not eligible for the trial. However, 
patients who achieve CR or PR as a result of therapy on this trial may proceed to 
allogeneic transplant. 
• 
Patients may not receive any other anti-cancer therapy (cytotoxic, biologic, 
radiation, or hormonal other than for replacement) while on this study other than 
hydroxyurea for control of counts. 
• 
Human Immunodeficiency Virus (HIV)-positive. 
 
3.3    Study Treatments 
 
3.3.1  
Clinical Trial Materials 
VELCADE® (bortezomib) for Injection is a sterile lyophilized powder for reconstitution and is 
supplied in vials containing VELCADE and mannitol at a 1:10 ratio.  For example, vials 
containing 3.5 mg of VELCADE contain 35 mg of mannitol. 
 
Doxil (Pegylated liposomal doxorubicin) is a sterile, translucent, red liposomal dispersion 
provided in single use glass vials. Each vial contains 20 mg/ 10 ml of doxorubicin HCL or 50 
mg/25ml of doxorubicin HCL at a concentration of 2mg/ml. 
 
Lipodox is a drug with the same active ingredient, dosage, strength, and route of 
administration as Doxil, and Lipodox is manufactured in a facility that has been inspected 
by FDA and found to be in compliance with current good manufacturing practices. Lipodox 
has not been approved by FDA, and therefore, FDA cannot consider it a "generic" of Doxil. 
The agency has exercised enforcement discretion for the importation of Lipodox during the 
critical shortage of Doxil. 
 
Decitabine for Injection contains decitabine (5-aza-2’-deoxycitidine), an analogue of the 
natural nucleoside 2’-deoxycytidine. Decitabine is a fine, white to almost white powder with 
the molecular formula of C8H12N4O4 and a molecular weight of 228.21. Its chemical name 
is 4-amino-1-(2-deoxy-β- D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one. Decitabine is 
slightly soluble in ethanol/water (50/50), methanol/water (50/50) and methanol; sparingly 
soluble in water and soluble in dimethylsulfoxide (DMSO). Decitabine for Injection is a white 
to almost white sterile lyophilized powder supplied in a clear colorless glass vial. Each 20 
mL, single dose, glass vial contains 50 mg decitabine, 68 mg monobasic potassium 
phosphate (potassium dihydrogen phosphate) and 11.6 mg sodium hydroxide. Please refer 


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to the package insert for decitabine (Appendix 8.10) for details. 
 
The commercial supply of Doxil and decitabine will be used for this study. 
3.3.2    
Preparation, Handling, Storage, and Destruction of Drugs  
VELCADE 
Vials containing lyophilized VELCADE® (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); for Europe, do not store above 30ºC (86ºF); excursions 
permitted from 15 to 30ºC (59-86ºF).  To date, stability data indicate that the lyophilized 
drug product is stable for at least 18 months when stored under the recommended 
conditions.  Stability studies are ongoing, and Millennium Pharmaceuticals, Inc. will notify 
the investigator should this information be revised during the conduct of the study. 
VELCADE is cytotoxic.  As with all cytotoxic drugs, caution is required when preparing and 
handling VELCADE solutions.  Cytotoxic drugs should only be handled by staff specially 
trained in the safe handling of such preparations.  The use of gloves and other appropriate 
protective clothing is recommended.  In case of skin contact, wash the affected area 
immediately and thoroughly with soap and water for at least 15 minutes.  If product contacts 
eye, immediately flush eye thoroughly with water for at least 15 minutes.  Always contact a 
physician after any 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 reconstitution the vials should remain in the cartons to protect them from light.  
Dissolution is completed in approximately 10 seconds.  The reconstituted solution is clear 
and colorless, with a final pH of 5 to 6.  Reconstituted VELCADE should be administered 
promptly and in no case more than 8 hours after reconstitution. 
Drug Administration and Dosage Schedule 
VELCADE Administration  
Velcade will be administered at 1.3mg/m2 SQ on days 5, 8, 12 and 15 of a 4 week cycle 
during induction courses and at 1.3mg/m2 SQ on days 1, and 8 of a 4 week cycle during 
post-induction courses. 
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. 


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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 (see Appendix 8.3).  The dose should be 
calculated on Day 1 of each cycle; the dose administered should remain the same 
throughout each cycle but should be recalculated at the start of the next cycle.  If a patient 
experiences a >10% 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 VELCADE. 
Intravenous and subcutaneous route of administration have different reconstituted 
concentration. Caution should be used when calculating the volume to be administered. 
Reconstitution1;2: Different volumes of diluent were used to reconstitute the product for the 
different routes of administration. The reconstituted concentration of bortezomib for SC 
administration (2.5 mg/mL) was greater than the reconstituted concentration of bortezomib 
for IV administration (1.0 mg/mL). See Table 3-1 below. 
 
Table 3-1. Reconstitution and Final Concentration of  Bortezomib (3.5 mg Vial) 
 
 
IV 
SC 
Volume of diluent  
(normal [0.9%] saline) 
3.5 mL 
1.4 mL 
Final bortezomib 
concentration 
1 mg/mL 
2.5 mg/mL 
 
SUBCUTANEOUS ADMINISTRATION:  
Drug is available in sterile, single use vials containing 3.5 mg of VELCADE.  Each vial of 
VELCADE for Injection should be reconstituted under a laminar flow biological cabinet 
(hood) within eight hours before dosing with 1.4 mL of normal (0.9%) saline, Sodium 
Chloride Injection USP, so that the reconstituted solution contains VELCADE 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.  


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• 
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 VELCADE administration 
subcutaneously, a less concentrated VELCADE 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 VELCADE IV, local skin irritation was reported in 5% of patients, 
but extravasation of VELCADE was not associated with tissue damage. In a clinical 
trial of subcutaneous VELCADE, a local reaction was reported in 6% of patients as 
an adverse event, mostly redness.  
VELCADE Destruction 
Investigational VELCADE (expired or end of study) should be destroyed on site according 
to the institution’s standard operating procedure.  Be sure to document removal and 
destruction on drug accountability logs. 
Doxil or LipoDox 
Handling instructions for the preparation of Doxil or LipoDox (pegylated liposomal 
doxorubicin) solution for intravenous administration 
 
Pegylated liposomal doxorubicin is a sterile, translucent, red liposomal dispersion provided 
in single use glass vials. Each vial contains 20 mg/ 10 ml of doxorubicin HCL or 50 mg/25ml 
of doxorubicin HCL at a concentration of 2mg/ml. 
 
Caution should be exercised in the handling and preparation of pegylated liposomal 
doxorubicin: 
• 
Use of gloves is required. 
• 
If pegylated liposomal doxorubicin comes into contact with skin or mucosa, immediately 
wash thoroughly with soap and water. 
• 
Pegylated liposomal doxorubicin should be considered an irritant and precautions 
should be taken to avoid extravasation. With intravenous administration, extravasation 
may occur with or without an accompanying stinging or burning sensation, even if blood 
returns well on aspiration of the infusion needle. If any signs or symptoms of 


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extravasation have occurred, the infusion should be immediately terminated and 
restarted in another vein. 
• 
Pegylated liposomal doxorubicin must not be given by the intramuscular or 
subcutaneous route. 
• 
Refrigerate at 2°-8°C. Avoid freezing. 
• 
Pegylated liposomal doxorubicin should be handled and disposed of in a manner 
consistent with other anticancer drugs. 
Doxil or Lipodox Administration 
The appropriate dose of pegylated liposomal doxorubicin, up to 90 mg, must be diluted in 
250 mL of 5% Dextrose Injection, USP prior to administration. Doses exceeding 90 mg 
should be diluted in 500 ml of 5% Dextrose Injection, USP prior to administration. Aseptic 
technique must be strictly observed since no preservative or bacteriostatic agent is present 
in pegylated liposomal doxorubicin. The diluted preparation must be refrigerated at 2°C to 
8°C (36°F to 46°F) and administered within 24 hours. 
• 
Do not use with in-line filters. 
• 
Do not mix with other drugs. 
• 
Do not mix with any diluent other than 5% Dextrose Injection. 
• 
Do not use any bacteriostatic agent, such as benzyl alcohol. 
 
Pegylated liposomal doxorubicin is not a clear solution but a translucent, red liposomal 
dispersion. 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Do not use if a 
precipitate or foreign matter is present. 
Rapid flushing of the infusion line should be avoided. 
Doxil or LipoDox Dosage and Administration 
Pegylated liposomal doxorubicin will be administered once every four weeks as a single 
intravenous infusion at a dose of 40 mg/m2 (day 12 of each cycle), at an initial rate of 1 
mg/min to minimize the risk of infusion reactions. If no infusion-related AEs are observed, 
the rate of infusion can be increased to complete administration of the drug over one hour. 
Body surface area (BSA) calculation will be based on actual body weight. Dose 
adjustments should be made for any change in body weight >10% occurring throughout the 
study. Patients seen to be benefiting from treatment with pegylated liposomal doxorubicin 
may continue to receive treatment once every three weeks until satisfactory response (CR, 
PR, SD), progression of disease, unacceptable toxicity, or death occurs or defined in the 
protocol. At all times, the investigator may discontinue the subject from the study at his or 


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her discretion for any reason. To manage adverse events such as hand-foot syndrome 
(HFS), stomatitis, or hematologic toxicity, the dose may be delayed or reduced. 
 
Injection Site Effects 
Pegylated liposomal doxorubicin is not a vesicant, but should be considered an irritant and 
precautions should be taken to avoid extravasation. With intravenous administration of 
pegylated liposomal doxorubicin, extravasation may occur with or without an accompanying 
stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. 
If any signs or symptoms of extravasation have occurred, the infusion should be 
immediately terminated and restarted in another vein. The application of ice over the site of 
extravasation for approximately 30 minutes may be helpful in alleviating the local reaction. 
Pegylated liposomal doxorubicin must not be given by the intramuscular or subcutaneous 
route. 
 
Infusion reactions 
Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions 
have been reported with pegylated liposomal doxorubicin. Medications to treat such 
reactions, as well as emergency equipment, should be available for immediate use. These 
reactions were characterized by one or more of the following symptoms: flushing, shortness 
of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and 
throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, 
apnea, and hypotension. In most patients, these reactions resolve over the course of 
several hours to a day once the infusion is terminated. In some patients, the reaction 
resolved when the rate of infusion was slowed. The majority of infusion-related events 
occur during the first infusion. Similar reactions have not been reported with conventional 
doxorubicin and they presumably represent a reaction to the pegylated liposomal 
doxorubicin liposomes or one of its surface components. The initial rate of infusion should 
be 1 mg/min to help minimize the risk of infusion reactions. 
 
Storage and Stability 
Refrigerate unopened vials of pegylated liposomal doxorubicin at 2°C to 8°C (36°F to 46°F). 
Avoid freezing. Prolonged freezing may adversely affect liposomal drug products; however, 
short-term freezing (less than 1 month) does not appear to have a deleterious effect on 
pegylated liposomal doxorubicin. 
Decitabine 
Please refer to the decitabine package insert (Appendix 8.10) for details regarding 
preparation, handling, storage and destruction of decitabine. 
 
DECITABINE for Injection is supplied as a sterile, lyophilized white to almost white powder, 


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in a single-dose vial, packaged in cartons of 1 vial. Each vial contains 50 mg of decitabine. 
 
DECITABINE is a cytotoxic drug and caution should be exercised when handling and 
preparing DECITABINE. Procedures for proper handling and disposal of antineoplastic 
drugs should be applied. Several guidances on this subject have been published. 
DECITABINE should be aseptically reconstituted with 10 mL of Sterile Water for Injection 
(USP); upon reconstitution, each mL contains approximately 5.0 mg of decitabine at pH 6.7-
7.3. Immediately after reconstitution, the solution should be further diluted with 0.9% 
Sodium Chloride Injection or 5% Dextrose Injection to a final drug concentration of 0.1‑1.0 
mg/mL. Unless used within 15 minutes of reconstitution, the diluted solution must be 
prepared using cold (2˚C ‑ 8˚C) infusion fluids and stored at 2˚C ‑ 8˚C (36˚F ‑ 46˚F) for up 
to a maximum of 4 hours until administration. Parenteral drug products should be inspected 
visually for particulate matter and discoloration prior to administration, whenever solution 
and container permit. Do not use if there is evidence of particulate matter or discoloration. 
 
NDC 62856-600-01, 50 mg single-dose vial individually packaged in a carton. Store vials at 
25°C (77°F); excursions permitted to 15-30°C (59-86°F). 
 
Decitabine will be administered at 20mg/m2 IV on days 1-10 of a 28-day cycle during 
induction cycles and at 20mg/m2 IV on days 1-5 of a 28-day cycle during post-induction 
therapy cycles (as described in Section 3.1). 
 
3.3.3   Dose Modifications and Delays 
SQ Velcade Dose Modification and Delay 
Before each drug dose, the patient will be evaluated for possible toxicities that may have 
occurred after the previous dose(s).  Toxicities are to be assessed according to the NCI 
Common Toxicity Criteria for Adverse Events (CTCAE), Version 4.0  
All previously established or new toxicities observed any time and that are related to 
VELCADE are to be managed as described in Table 3-2  Neuropathic pain and peripheral 
sensory neuropathy are to be managed separately as described in Table 3-3. 
Table 3-2    
Toxicity Management 
Toxicity 
Grade 
Action 
Nonhematological toxicity 
3 
Hold Velcade therapy 
Hematological Toxicity 
Any 
None  
 


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For grade 3 nonhematologic toxicities related to VELCADE, VELCADE is to be held until 
the toxicity returns to Grade 1 or better. 
Once VELCADE is reduced for any toxicity, the dose may not be re-escalated. 
If after VELCADE has been held, the VELCADE-related toxicity does not resolve to Grade 1 
or better, then VELCADE must be discontinued. Per investigator discretion, the patient may 
continue on protocol therapy without VELCADE. 
If the toxicity resolves, as described above, VELCADE 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 unless patient is responding, in 
which case, this should be discussed with the principal investigator. 
Patients who experience SQ VELCADE-related neuropathic pain or peripheral sensory 
neuropathy are to be managed as presented in Table 3-3.  Once the dose is reduced for 
peripheral neuropathy, the dose may not be re-escalated. 


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Table 3-3    
Management of Patients With VELCADE-Related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy  
Severity of Peripheral Neuropathy Signs 
and Symptoms a 
Modification of Dose and Regimen 
Grade 1 (asymptomatic; loss of deep tendon 
reflexes or  paresthesias) without pain or loss 
of function 
No action 
Grade 1 with pain or Grade 2 (moderate 
symptoms; limiting instrumental Activities or 
Daily Living [ADL])b) 
Reduce VELCADE to 1.0 mg/m2 
Grade 2 with pain or Grade 3 (severe 
symptoms; limiting self care ADLc) 
Withhold VELCADE therapy until toxicity resolves 
to grade 1. When toxicity resolves reinitiate with a 
reduced dose of VELCADE at 0.7 mg/m2. If 
toxicity does not resolve, discontinue VELCADE. d 
Grade 4 (life-threatening consequence; 
urgent intervention indicated) 
Discontinue VELCADEd 
Source:  VELCADE 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 
d  Per investigator discretion, the patient may continue on protocol therapy without VELCADE. 
 
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 due to Gilbert’s Syndrome).  If a patient develops 
moderate or severe hepatic impairment with bilirubin ≥ Grade 2 (> 1.5 -3.0 × ULN) while on 
study, the investigator should hold VELCADE until the toxicity returns to < Grade 2. 
Restarting VELCADE at the next lower dosed level could be considered at the 
Investigator’s discretion and following exclusion of VELCADE-induced liver impairment and 
careful consideration of liver disease due to other causes. 
Doxil or LipoDox Dose Modification and Delay 
Patients treated with pegylated liposomal doxorubicin (PLD) should be carefully monitored 
for toxicity. Following the first appearance of a Grade 2 or higher adverse event related to 
PLD, the PLD dosing should be adjusted or delayed as described in Table 3-4. Once the 
dose has been reduced, it should not be increased at a later time (Doxil® Product 
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In general, most adverse events are manageable with dose reductions or delays. 
Management of more specific toxicities (e.g. such as HFS, hematologic toxicities, and 
stomatitis, which may be managed by dose delays and adjustments) are outlined in the 
relevant sections of the protocol. Pegylated liposomal doxorubicin exhibits nonlinear 
pharmacokinetics at 40 mg/m2; therefore, dose adjustments may result in a non-
proportional greater change in plasma concentration and exposure to the drug. 
 
Table 3-4 Pegylated liposomal doxorubicin dose adjustment guideline for PLD-
related toxicities 
Toxicity 
CTC Grade 
Actions 
Hand Foot 
Syndrome 
Grade 1 (mild erythema, 
swelling, 
or desquamation not 
interfering 
with daily activities) 
Re-dose, unless patient has experienced previous Grade 
3 or 4 toxicity. If so, delay up to 2 weeks and decrease 
dose by 25%. Return to original dose interval. 
 
Grade 2 (erythema, 
desquamation, or 
swelling interfering with, 
but not precluding 
normal physical 
activities; small blisters 
or ulcerations less than 
2cm in diameter.) 
Delay dosing for up to 2 weeks or until resolved to Grade 
0-1. If after 2 weeks there is no resolution, pegylated 
liposomal doxorubicin should bediscontinued. If resolved 
to Grade 0-1 within 2 weeks, and there was no prior 
Grade 3-4 HFS, continue treatment at previous dose and 
return to original dose 
interval. If patient experienced previous Grade 3-4 
toxicity, continue treatment with a 25% dose reduction 
and return to original dose interval. 
 
Grade 3 (blistering, 
ulceration, or swelling 
interfering with walking 
or normal daily activities; 
cannot wear regular 
clothing) 
Delay dosing up to 2 weeks or until resolved to Grade 0-
1. Decrease dose by 25% and return to original dose 
interval. If after 2 weeks there is no resolution, pegylated 
liposomal doxorubicin should be discontinued. 
 
Grade 4 (diffuse or local 
process causing 
infectious complications, 
or a bed ridden state or 
hospitalization) 
Delay dosing up to 2 weeks or until resolved to Grade 0-
1. Decrease dose by 25% and return to original dose 
interval. If after 2 weeks there is no resolution, pegylated 
liposomal doxorubicin should be discontinued. 
Hematologic 
toxicity (ANC, 
Platelets) 
Any Grade 
None 
Stomatitis 
Grade 1 (painless ulcers, 
erythema, or mild 
soreness) 
Redose unless patient has experienced previous Grade 
3 or 4 toxicity. If so, delay up to 2 weeks and decrease 
dose by 25%. Return to original dose interval 
 
Grade 2 (painful 
erythema, 
edema, or ulcers, but 
can eat) 
Delay dosing up to 2 weeks or until resolved to Grade 0-
1. If after 2 weeks there is no resolution, pegylated 
liposomal doxorubicin should be discontinued. If 
resolved to Grade 0-1 within 2 weeks, and there was 
no prior Grade 3-4 stomatitis, continue treatment at 
previous dose and return to original dose interval. If 
patient experienced previous Grade 3-4 toxicity, continue 
treatment with a 25% dose reduction and 
return to original dose interval. 


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Grade 3 (painful 
erythema, 
edema, or ulcers, and 
cannot eat) 
Delay dosing up to 2 weeks or until resolved to Grade 0-
1. Decrease dose by 25% and return to original dose 
interval. If after 2 weeks there is no resolution, pegylated 
liposomal doxorubicin should be discontinued. 
 
Grade 4 (requires 
parenteral  support) 
Delay dosing up to 2 weeks or until resolved to Grade 0-
1. Decrease dose by 25% and return to pegylated 
liposomal doxorubicin original dose interval. If after 2 
weeks there is no resolution, pegylated liposomal 
doxorubicin should be discontinued. 
Diarrhea 
Grade 2 
Hold dose until recovery to Grade 0 then continue at 
current dose level. If grade 2 toxicity persists for more 
than 14 days 
beyond the date of the next intended dose, decrease the 
next scheduled 
 
Grade 3 
Hold dose until recovery to Grade 0 then continue at 
current dose level. 
If grade 3 toxicity lasts longer than 3 days despite 
maximal medical attention to diarrhea decrease the next 
scheduled dose by 25% after resolution to Grade 0. 
If toxicity recurs and lasts longer than 3 days despite 
maximal medical attention to diarrhea, decrease original 
dose by 50% after resolution to Grade 0. If toxicity recurs 
again then discontinue treatment. 
 
Grade 4 
Hold dose until recovery to Grade 0. 
In the event toxicity lasts >24 hours despite maximal 
medical attention discontinue treatment. If grade 4 
toxicity lasts <24 hours reduce dose by 25% at next 
cycle. 
If toxicity recurs discontinue treatment. 
 
Patients with febrile neutropenia 
Patients developing febrile neutropenia during the course of study must be managed as per 
local institutional guidelines and is an expected event in patients with AML. For patients 
who develop febrile neutropenia, Doxil should either be held (if febrile neutropenia occurs 
before the scheduled dose), or dose reduced by 25% for the next cycle (if febrile 
neutropenia occurs after Doxil administration). 
 
Table 3-5 Dose adjustment of pegylated liposomal doxorubicin in hepatically 
impaired patients 
 
Serum Bilirubin (x ULN) 
Dose Adjustment 
1.2 – 3.0 mg/dL 
Decrease dose by 25% 
>3 mg/dL 
Decrease dose by 50% 
 
 
AST/ALT (x ULN) 
Dose Adjustment 
>3-5 times ULN 
Decrease dose by 25% 
>5 times ULN 
Decrease dose by 50% 
 
 


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Cardiac toxicity 
Cardiac function should be carefully monitored in patients treated with pegylated liposomal 
doxorubicin. (Doxil® Product Information Booklet 2005) The use of pegylated liposomal 
doxorubicin injection may lead to cardiac toxicity. Acute left ventricular failure can occur, 
particularly in patients who have received total dosage exceeding the currently 
recommended limit of 550 mg/m2. Lower doses (400 mg/m2) appear to cause heart failure 
in patients who have received prior radiotherapy to the mediastinal area or are receiving 
concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. 
Pegylated liposomal doxorubicin should be administered to patients with a history of 
cardiovascular disease only when the potential benefit outweighs the risk, and cardiac 
function should be carefully monitored. All patients who enroll in the study are required to 
have a MUGA scan or a 2-D echocardiogram performed at screening (within 30 days prior 
to start of study medication), every two cycles starting with Cycle 7 (e.g., pre-Cycle 7, 9, 11, 
and End of Study Treatment. The LVEF value at screening must be >=50%. All MUGA/2-D 
echocardiograms must be recorded on video and maintained at the site. During treatment 
with pegylated liposomal doxorubicin, when a patient has reached a total (lifetime 
cumulative) anthracycline dose of 300 mg/m2, follow-up MUGA scans or 2-D 
echocardiograms are to be performed every two cycles (and this schedule will replace the 
schedule of assessments every two cycles after Cycle 6 listed above for applicable 
patients). Additional evaluations may be performed throughout the trial as clinically 
indicated for patients receiving pegylated liposomal doxorubicin to monitor cardiac toxicity. 
If left ventricular ejection fraction declines to less than 45% or a decrease by an absolute 
value of 20% from the baseline value is noted, treatment with pegylated liposomal 
doxorubicin is to be temporarily suspended or discontinued and restarted at investigator 
discretion.43 For subjects in CR continuing on post-induction therapy per protocol, pegylated 
liposomal doxorubicin should be discontinued once the total lifetime doxorubicin (or 
equivalent) dose of 550 mg/m2 is reached or a maximum of 12 cycles. These subjects may 
continue on protocol therapy without pegylated liposomal doxorubicin at investigator 
discretion. 
 
Other toxicities 
If a patient in the pegylated liposomal doxorubicin arm experiences any other Grade 3 or 4 
non-hematologic toxicity related to PLD, PLD should be held until the toxicity resolves to < 
Grade 2 and subsequent doses of Doxil should be dose reduced by 25%. If the ≥ Grade 3 
toxicity recurs, PLD must be discontinued. These subjects may continue on protocol 
therapy without pegylated liposomal doxorubicin at investigator discretion. 
 
 
 


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Decitabine Dose Modification and Delay 
Induction: 
Grade 3 non-hematologic toxicities from cycle 1 should resolve to grade 2 or better before 
starting subsequent induction cycles of decitabine. Subsequent cycles of induction may be 
delayed at investigator discretion up to 14 days or to allow for resolution of non-hematologic 
toxicities to grade 2 or better. There are no hematologic parameters for administration of 
induction cycles of decitabine, since subjects have active AML and blood count recovery is 
not expected  
Post-Induction: 
Grade 3 non-hematologic toxicities from prior cycles should resolve to grade 2 or better 
before starting subsequent post-induction cycles of decitabine. 
Following a 5-day course of decitabine, subjects without evidence of AML (defined as no 
minimal residual disease by flow cytometry, cytogenetics or molecular markers), but who 
had grade 4 neutropenia (<500/µL) of at least a 14-day duration will receive a dose 
reduction of decitabine to 4 days with the next cycle. A second dose reduction of decitabine 
to 3 days per cycle is permitted if grade 4 neutropenia of at least a 14-day duration occurs 
again. Patients with residual AML (defined as presence of minimal residual disease by flow 
cytometry, cytogenetics or molecular markers), however, will continue to receive 5 days of 
decitabine per cycle. Subsequent cycles of post-induction may be delayed at investigator 
discretion up to 14 days or to allow for resolution of non-hematologic toxicities to grade 2 or 
better and to allow neutrophils to recover to greater than 1000/µL and platelets to greater 
than 100,000/µL in patients with CR. There are no hematologic parameters for 
administration of post-induction cycles of decitabine in patients with persistent AML or in 
CRi. 
3.3.4  Treatment Assignment  
N/A 
3.3.5 Blinding, Packaging, and Labeling 
VELCADE will be supplied in vials as open-label stock.  Both the box label and vial label will 
fulfill all requirements specified by governing regulations. 
3.3.6    
Concomitant Treatment  
Investigators should consider using antiviral prophylaxis in subjects being treated with 
VELCADE. 


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Standard supportive care includes the use of, growth factors, packed red blood cells 
(PRBC) and platelets, admission for intravenous fluids and antimicrobial therapy as per the 
discretion of the treating physician. Hydroxyurea is permitted during cycle 1 of induction to 
control the white blood cell count. 
3.3.7 Prohibited Concurrent Therapy  
• 
Participation in clinical trials with other investigational agents, not included in this 
trial, within 14 days of the start of this trial and throughout the duration of this trial. 
3.3.8   
Treatment Compliance 
All drugs 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 8.3), 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. 
3.3.9    
Precautions and Restrictions 
It is not known what effects VELCADE 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.  Non-
sterilized 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 SQ VELCADE, or agree to completely abstain from 
heterosexual intercourse. 
 
 


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It is strongly recommended that at least 1 of these 2 methods be highly effective (see 
examples below). 
Highly effective methods 
Other effective methods 
(barrier methods) 
Intra-uterine devices (IUD) 
Latex condom 
Hormonal contraceptives (birth control 
pills/oral contraceptives, injectable 
contraceptives, contraceptive patches, or 
contraceptive implants) 
Diaphragm with spermicide 
Cervical cap 
Sponge 
If one of the highly effective methods cannot be used, using 2 effective 
methods at the same time is recommended.  
 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following: 
• 
Practice effective barrier contraception during the entire study treatment period and 
through a minimum of 30 days after the last dose of study drug, or completely 
abstain from heterosexual intercourse. 
3.4    
Duration of Treatment and Patient Participation 
Patients will receive a minimum of 1 cycles and a maximum of 4 cycles of induction. If there 
is no response or if they have a DLT, they will be taken off the study. Patients will receive 
continued cycles of post-induction therapy until progression, intolerance, transplant, 
withdrawal of informed consent or a total of 12 cycles (including induction cycles) are 
administered. 
 
 
3.5    Termination of Treatment and/or Study Participation 
Patients must 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, and in some cases is required to withdraw, patients from the study for any of 
the following reasons: 
• 
Intercurrent illness 
• 
Occurrence of an unacceptable adverse event 
• 
A significant treatment cycle delay or SQ VELCADE interruption, at the 
investigator’s discretion. 
• 
Protocol violations 


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• 
Noncompliance 
• 
Administrative reasons 
• 
Failure to return for follow-up 
• 
General or specific changes in the patient’s condition unacceptable for further 
treatment in the judgment of the investigator 
• 
Progressive disease at any time 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed.  The primary reason for a patient’s withdrawal from the study is to be recorded 
in the source documents. 
3.6    Efficacy  
3.6.1    
Efficacy Measurements  
All patients who are registered will be accounted for in the report of the results. To be 
evaluable for toxicity, a patient must receive at least one cycle of treatment and or have 
experienced a DLT in the first cycle. All patients who receive the first cycle of treatment will 
be included in the analysis of progression free and overall survival. Treatment efficacy will 
be determined by complete blood counts and bone marrow biopsy after each cycle of 
induction. 
 
 
Definitions  
Response and progression will be evaluated in this study using the Revised 
Recommendations of the International Working Group for Diagnosis, 
Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. 
 
Measurable disease  
Not applicable  
 
Response Criteria- leukemia  
The following categories from the Revised Recommendations of the 
International Working Group will be used: Morphologic leukemia-free state: Less 
than 5% blasts in an aspirate sample with marrow spicules and with a count of 
at least 200 nucleated cells. There are no Auer rods or persistence of 


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extramedullary disease. (The presence of a unique phenotype by flow cytometry 
identical to what was found in the pre-treatment specimen is viewed as 
persistence of leukemia [minimal residual disease]) Morphologic complete 
remission (CR): The patient achieves the morphologic leukemia-free state and 
has an absolute neutrophil count of > 1000/uL and platelet count ≥ 100,000/uL. 
The patient is independent of blood transfusions. No duration of response is 
required to fulfill these criteria. Cytogenetic complete remission (CRc): Patients 
who achieve a morphologic CR along with reversion to a normal karyotype by 
cytogenetic analysis. For patients who have unique markers by routine 
cytogenetics or by FISH upon enrollment, these markers will be followed on 
subsequent bone marrow examinations using the same technique(s) to evaluate 
for CRc. Molecular complete remission (CRm): Patients who achieve a 
morphologic CR with no residual disease by molecular or flow cytometric 
detection methods. For patients with unique multi-dimensional flow cytometry 
markers at the time of enrollment, these will be repeated on subsequent bone 
marrow studies to evaluate for CRm.  Morphologic CR with incomplete blood 
count recovery (CRi): Patient fulfill the criteria for morphologic CR except for 
residual neutropenia (<1000/uL) and/or thrombocytopenia (<100,000/uL).  
 
Partial Remission (PR): This requires the same hematologic values for a CR but 
with a decrease of at least 50% in the percentage of blasts to a post-treatment 
value of 5% to 25% in the bone marrow aspirate. (If the pre-treatment blast 
percentage was 50-100%, this must decrease to a value between 5-25%. If the 
pre-treatment blast percentage was 20-49%, this must decrease by at least half 
to a value greater than 5%). A value ≤ 5% is also considered a PR if Auer rods 
are present.  
 
Treatment Failure: 
 
Resistant disease: Patient does not achieve CR, CRi or PR upon repeat bone 
marrow examination after 2-4 cycles of induction therapy, persistent AML in 
blood or bone marrow.  
 
Aplasia: Patient dies, death occurs while cytopenic with aplastic bone marrow.  
 
Indeterminate cause: Patient dies with no blasts in peripheral blood but no bone 
marrow examination; Patient does not complete the first course of therapy.  
 


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Morphologic relapse: reappearance of blasts post-CR in peripheral blood or 
bone marrow. 
 
 Molecular or cytogenetic relapse: Reappearance of the molecular or 
cytogenetic abnormality  
 
Duration of overall response-leukemia: The duration of overall response is 
measured from the time measurement. Criteria are met for CR or PR (whichever 
is first recorded) until the first date that treatment failure is objectively 
documented. 
3.6.2    
Safety Measurements 
In addition to the requirements for adverse event reporting as outlined in section 6.0, this 
protocol is also subject to the UC Davis Cancer Center’s (UCDCC) Data and Safety 
Monitoring Plan. The UCDCC is committed to pursuing high-quality patient-oriented clinical 
research and has established mechanisms to ensure both scientific rigor and patient safety 
in the conduct of clinical research studies. The UCDCC relies on a multi-tiered committee 
system that reviews and monitors all cancer clinical trials and ensures the safety of its 
participants, in compliance with institutional and federal requirements on adverse event 
(AE) reporting, verification of data accuracy, and adherence to protocol eligibility 
requirements, treatment guidelines, and related matters. The Scientific Review Committee 
(SRC) assumes overall oversight of cancer studies, with assistance and input from two 
independent, but interacting, committees: the Quality Assurance Committee and the Data 
Safety Monitoring Committee. A multi-level review system strengthens the ability of the 
UCDCC to fulfill its mission in conducting high quality clinical cancer research. 
 
As per University of California Davis Cancer Center (UCDCC) Clinical Trials Support Unit 
(CTSU) SOP AM 506: Protocol Specific Meetings, the principal investigator (PI), clinical 
research coordinator (CRC), and the clinical research nurse meet at least monthly for 
ongoing study information, to discuss patient data and adverse events and to determine if 
dose escalation is warranted, when applicable.   
 
According to the UCDCC Data and Safety Monitoring Plan (DSMP), any new serious 
adverse events related to the drugs being used on this trial are reviewed monthly by the 
UCDCC Data and Safety Monitoring Committee (DSMC) and any applicable changes to the 
study are recommended to the PI, if necessary. 
 
The UCDCC Scientific Review Committee (SRC) determines if a UCDCC Data and Safety 
Monitoring Board (DSMB) is required.  If required, the DSMC will appoint a DSMB. The 


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DSMB is responsible for reviewing study accrual logs, adverse event information and dose 
escalation meeting minutes (where applicable) to ensure subject safety and compliance 
with protocol defined guidelines. 
4.    
ADVERSE EVENTS 
All serious adverse events (SAEs) (regardless of expectedness, causality, and whether 
commercial or investigational VELCADE is used) must be reported to Millennium 
Pharmacovigilance (or designee).  See Section 4.3 for the reporting of SAEs. 
The sponsor-investigator is responsible to meet all regulations and requirements applicable 
to the sponsor-investigator. 
4.1    Definitions 
4.1.1    Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug. 
For this protocol an abnormal laboratory value will not be assessed as an AE unless that 
value leads to discontinuation or delay in treatment, dose modification, therapeutic 
intervention, or is considered by the investigator to be a clinically significant change from 
baseline. 
Adverse Drug Reaction 
An adverse drug reaction (ADR) is a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. This includes adverse 
reactions which arise from: use of a medicinal product within the terms of the marketing 
authorization; use outside the terms of the marketing authorization, including overdose, 
misuse, abuse and medication errors; and occupational exposure*. 


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* This corresponds to the exposure to a medicinal product for human use as a result of 
one’s occupation, such as nurses who may handle products routinely in their occupational 
setting. 
4.1.2    Serious Adverse Event Definition 
Serious adverse event (SAE) means any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification below on planned hospitalizations in Section 4.2). 
• 
Results in persistent or significant disability or incapacity.  (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent one of the outcomes listed above, 
or involves suspected transmission via a medicinal product of an infectious agent.    
o Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. 
o With respect to the suspected transmission via a medicinal product of an 
infectious agent; any organism, virus, or infectious particle (e.g., prion 
protein transmitting Transmissible Spongiform Encephalopathy), whether 
pathogenic or non-pathogenic, is considered an infectious agent.   
Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous.  The general term severe is often used to describe the intensity (severity) of a 
specific event; the event itself, however, may be of relatively minor medical significance 


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(such as a Grade 3 headache).  This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function.  A severe AE (Grade 3 or 4) 
does not necessarily need to be considered serious.  For example, a white blood cell count 
of 1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered 
serious.  Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations. 
4.2    Procedures for Reporting Serious Adverse Events (SAEs) 
Adverse events (AEs) may be spontaneously identified by the patient and/or in response to 
an open question from study personnel or revealed by observation, physical examination, 
or other diagnostic procedures.  Any clinically relevant deterioration in laboratory 
assessments or other clinical finding is considered an AE.  AEs which are serious must be 
reported to Millennium Pharmacovigilance (or designee) from first dose of VELCADE up to 
and including 30 days after administration of the last dose of VELCADE.  When possible, 
signs and symptoms indicating a common underlying pathology should be noted as one 
comprehensive event.   
Adverse Events which are serious must be reported to Millennium Pharmacovigilance (or 
designee) from the first dose of bortezomib up to and including 30 days after administration 
of the last dose of bortezomib. Any SAE that occurs at any time after completion of 
VELCADE treatment or after the designated follow-up period that the investigator and/or 
sponsor-investigator considers to be related to any study drug must be reported to the 
Millennium Pharmacovigilance (or designee).  Planned hospital admissions or surgical 
procedures for an illness or disease that existed before the patient was enrolled in the trial 
are not to be considered AEs unless the condition deteriorated in an unexpected manner 
during the trial (e.g., surgery was performed earlier or later than planned).  All SAEs should 
be monitored until they are resolved or are clearly determined to be due to a patient’s stable 
or chronic condition or intercurrent illness(es). 
Since this is an investigator-initiated study, the principal investigator Joseph Tuscano, MD, 
also referred to as the sponsor-investigator, is responsible for reporting serious adverse 
events (SAEs) to any regulatory agency and to the sponsor- investigator’s EC or IRB.   
Regardless of expectedness or causality, all SAEs must also be reported in English to 
Millennium Pharmacovigilance or designee. Fatal and Life Threatening SAEs within 24 
hours of the sponsor-investigator’s observation or awareness of the event. 
All other serious (non-fatal/non-life threatening) events within 5 calendar days of the 
sponsor-investigator’s observation or awareness of the event.   


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See below for contact information for the reporting of SAEs to Millennium 
Pharmacovigilance.   
The sponsor-investigator must fax the SAE Form per timelines above. A sample of an SAE 
Form will be provided. 
The SAE report must include at minimum: 
• 
Event term(s) 
• 
Serious criteria 
• 
Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s determination. 
Intensity for each SAE, including any lab abnormalities, will be determined by using 
the NCI CTCAE version specified in the protocol, as a guideline, whenever possible.  
The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
• 
Causality of the event(s) and): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration.  
Follow-up information on the SAE may be requested by Millennium (or designee).   
Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI 
CTCAE version used at your institution, as a guideline, whenever possible.  The criteria are 
available online at http://ctep.cancer.gov/reporting/ctc.html. 
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure 
that the SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites 
participating in the study.  Sub-investigators must report all SAEs to the sponsor-
investigator so that the sponsor-investigator can meet his/her foregoing reporting 
obligations to the required regulatory agencies and to Millennium Pharmacovigilance, 
unless otherwise agreed between the sponsor-investigator and sub-investigator(s).   
Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that 
the AE is associated with the study drug(s)? 
US and Canada 
Toll-Free Fax Number: 1-800-963-6290  
Email: TakedaOncoCases@cognizant.com 
 
 


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Suggested Reporting Form: 
• 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
• 
Any other form deemed appropriate by the sponsor-investigator 
All serious, unlabeled, (unexpected) adverse events will be reported to the FDA as required 
by 21 CFR 312.32 on the FDA MedWatch 3500a form. (Investigational New Drug) 
https://www.accessdata.fda.gov/scripts/medwatch/. 
Reporting to the Institutional Review Board 
Both serious and non-serious adverse events will be reported in accordance with UCD IRB 
Administration and UCD Cancer Center Clinical Trial Support Unit (CTSU) policies. The UC 
Davis IRB can be reached at (916) 703-9151. 
4.3    Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug(s).  The sponsor-investigator must fax a completed Pregnancy Form (Appendix 8.10) 
or other approved equivalent form to the Millennium Pharmacovigilance or designee 
immediately (see Section 4.2). The pregnancy must be followed for the final pregnancy 
outcome (eg, delivery, still birth, miscarriage) and Millennium Pharmacovigilance will 
request this information from the sponsor-investigator. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a completed 
Pregnancy Form (Appendix 8.10) to the Millennium Pharmacovigilance or designee (see 
Section 4.2). Every effort should be made to follow the pregnancy for the final pregnancy 
outcome. 
5.    
STATISTICAL CONSIDERATIONS 
5.1    Study Design and Overview of Primary and Secondary Endpoints 
This is an open label, Phase II study in patients with relapse/refractory AML or previously 
untreated patients that are not candidates for standard induction therapy.  The primary 
endpoints are overall response rate and PFS. The secondary endpoints are overall survival 
and toxicity. There will be a safety lead-in to assess dose-limiting toxicities (DLTs) in the 
first 6-9 subjects described in Section 3.1. 


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5.2    Sample Size Estimation/Accrual Rate 
Up to 14 patients will be treated with decitabine, SQ VELCADE and doxil at dose levels 
previously established to be safe (including the two patients treated per the dosing 
schedule in Amendment 9). Fifteen patients have been treated to date through prior 
versions of this protocol with SQ bortezomib and peylated liposomal doxorubicin. Objective 
response (CR + CRi + PR) will be monitored using Simon’s minimax 2-stage design. This 
study design is optimal in the sense that it minimizes the expected sample size among 
competing designs. The OR rate in relapsed/refractory AML patients treated with a 10-day 
decitabine regimen is estimated to be approximately 16%. A 30% increase in the objective 
response rate with the addition of VELCADE and Doxil to 46% would justify evaluation of 
this regimen in larger, more definitive trials. We assume a one-sided type I error rate of 5% 
and desire at least 80% power to conclude that this regimen elicits an objective response 
rate significantly greater than 16% if the true response rate of this regimen is 46% or higher. 
Under these assumptions, if 2 or fewer OR’s are observed in the first 9 patients (which 
includes the two patients treated per the dosing schedule in Amendment 9), the principal 
investigator may conclude that regimen is insufficiently active to warrant further study. 
Otherwise, accrual will continue to a total of 14 patients. If 5 or more OR’s are observed in 
14 patients, this regimen will be deemed sufficiently active to warrant further study. 
 
The sample size determination and rules for the safety lead-in portion are described in 
detail in Section 3.1. 
5.3    Randomization and Stratification Factors 
N/A 
5.4    Evaluation of Efficacy 
Primary analyses of outcome variables will use the intent-to-treat dataset, defined as all 
eligible patients enrolled in the study. Secondary analyses will be restricted to patients 
receiving at least one study drug. The primary endpoint (objective response) will be 
summarized with frequency tables and 95% confidence intervals, and compared to stopping 
rules at the planned interim analysis and at final analysis. Continuous variables (e.g., age, 
hematology values, molecular studies/cytogenetics/Fluorescent in situ hybridization (FISH)) 
will be summarized using the mean (s.d.) or median (range). Frequency tables will be used 
to summarize categorical variables. Logistic regression will be used to assess the impact of 
patient characteristics (e.g., cytogenetics) on the objective response rate. The distribution of 
time-to-event endpoints (e.g., CR, PFS, overall survival) will be estimated using the method 
of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups of 
patients (based on known prognostic factors, e.g cytogenetics) will be made using the 


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logrank test. Cox (proportional hazards) regression will be used to evaluate multivariable 
predictive models of time-to-event outcomes. 
5.5    Evaluation of Safety 
Toxicity information recorded will include the type, severity, time of onset, time of resolution, 
and the probable association with the study regimen.  Tables will be constructed to 
summarize the observed incidence by severity and type of toxicity.   
Data from all subjects who receive any study drug will be included in the safety analyses. 
The severity of the toxicities will be graded according to the NCI CTCAE v4.0 whenever 
possible. Unacceptable toxicity experienced in patients will be monitored according to 
guidelines for monitoring toxicity in pilot/phase II trials using sequential probability ratio test 
based criteria.  The guidelines will be used to raise a flag if the number of patients who 
experience unacceptable toxicity is excessive is greater than 20%.  Toxicity information 
recorded will include the type, severity, time of onset, time of resolution, and the probable 
association with the study regimen. Tables will be constructed to summarize the observed 
incidence by severity and type of toxicity.  Baseline information (e.g. the extent of prior 
therapy, extent of disease) and demographic information will be presented, as well, to 
describe the patients treated in this Phase II study.   
 
6. ADMINISTRATIVE REQUIREMENTS 
6.1    Good Clinical Practice 
The study will be conducted in accordance with the International Conference on 
Harmonization (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.  This is the 
responsibility of the sponsor-investigator. 
6.2    Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration 
of Helsinki.  The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will 
review all appropriate study documentation in order to safeguard the rights, safety, and 
well-being of the patients.  The study will only be conducted at sites where IRB/IEC 


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approval has been obtained.  The protocol, Investigator’s Brochure, informed consent, 
advertisements (if applicable), written information given to the patients (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will 
be provided to the IRB/IEC by the investigator.  Millennium requests that the protocol and 
informed consent documents be reviewed by Millennium prior to IRB/IEC submission. 
Minorities and Gender Statement 
 
Recruitment is open to all minorities and both genders.  Although distributions may vary by 
disease type, our recruitment procedures have been developed to enroll patients who are 
representative of the respective target population.   
6.3    Patient Information and Informed Consent  
The principles of informed consent are described by Federal Regulatory Guidelines 
(Federal Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection 
from Research Risk Reports:  Protection of Human Subjects (Code of Federal Regulations 
45 CFR46).  They must be followed to comply with FDA regulations for the conduct and 
monitoring of clinical investigations. 
All patients will have signed an informed consent for participation in research activities in 
accordance with all institutional, NCI and Federal regulations, and will have been given a 
copy of the Experimental Subject's Bill of Rights. 
 
Once signed, informed consent has been obtained and all pretreatment evaluations have 
been performed, patients will be entered on study according to UCD Clinical Trials Support 
Unit (CTSU) policy. To register a patient, the research nurse or data manager must 
complete the Eligibility Checklist and the Patient Registration Form. A patient accession 
number will then be assigned.  Administration of study administration may not be initiated 
until the patient is registered. 
6.4    Institutional Review 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, 17, January 27, 1981, part 
56) and the Office for Protection from Research Risks Reports:  Protection of Human 
Subjects (Code of Federal Regulations 45 CFR 46). 


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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) from Millennium or its 
designees and regulatory authority(ies) access to the patient’s original medical records for 
verification of data gathered on the data capture records and to audit the data collection 
process.  The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
The original data collection forms will be stored in secure cabinets in the UCD Clinical Trials 
Support Unit. 
6.6    Protocol Compliance 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies).  
Changes to the protocol will require approval from Millennium and written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed 
to eliminate an immediate hazard(s) to patients.  The IRB/IEC may provide, if applicable 
regulatory authority(ies) permit, expedited review and approval/favorable opinion for minor 
change(s) in ongoing studies that have the approval /favorable opinion of the IRB/IEC.  The 
investigator will submit all protocol modifications to Millennium and the regulatory 
authority(ies) in accordance with the governing regulations. 
Any departures from the protocol must be fully documented in the source documents. 
Deviations in eligibility criteria are not allowed with the following exceptions: If the treating 
physician feels it is appropriate to request a deviation from the eligibility criteria, they must 
contact the PI to obtain approval.  If approved, the protocol PI must immediately submit an 
amendment to the protocol if the deviation is likely to occur again. In addition, the treating 
physician must request a waiver of eligibility according to current IRB policies. All protocol 
deviations will be reported in accordance with UCD IRB Administration and UCD Cancer 
Center CTSU policies 
6.7    On-site Audits 
Regulatory authorities, the IEC/IRB, and/or Millennium 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. 


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Quality assurance audits of select patients and source documents may be conducted by the 
UC Davis Cancer Center Quality Assurance Committee as outlined in the UC Davis Cancer 
Center Data and Safety Monitoring plan. 
 
Quality control will be maintained by the CTSU Quality Assurance team according to CTSU 
policy. 
6.8    Drug Accountability 
Accountability for the drug at all study sites (including all subsites, if applicable) is the 
responsibility of the sponsor-investigator.  The sponsor-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 will be maintained by the site 
and/or subsites.  Accountability records will include drug receipt/destruction dates, 
quantities, lot numbers, expiration dates (if applicable), and corresponding registered 
patient numbers. 
All material containing VELCADE will be treated and disposed of as hazardous waste in 
accordance with governing regulations. 
6.9    Product Complaints 
A product complaint is a verbal, written, or electronic expression that 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 Millennium  (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 
Millennium (see below) and report the event. 
For Product Complaints or Medication Errors,  
1-866-VELCADE (1-866-835-2233)  
E-mail: medical@mlnm.com 
FAX: 1-800-881-6092 
Hours: Mon-Fri, 9 a.m. – 7 p.m. ET 
 


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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 Millennium Pharmacovigilance (refer to Section 4.2). 
 
 
6.10    
Premature Closure of the Study  
This study may be prematurely terminated, if in the opinion of the sponsor-investigator or 
Millennium, there is sufficient reasonable cause.  Written notification documenting the 
reason for study termination will be provided to the sponsor-investigator or Millennium by 
the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to patients 
• 
Failure to enter patients at an acceptable rate 
• 
Insufficient adherence to protocol requirements 
• 
Insufficient complete and/or evaluable data 
• 
Plans to modify, suspend, or discontinue the development of the drug 
 
6.11    
Record Retention 
The sponsor-investigator will maintain all study records according to ICH-GCP and 
applicable regulatory requirement(s). 


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7.    
REFERENCES 
 
1  Dohner H, Estey EH, Amadori S, Applebaulm FR, Buchner T et al. Diagnosis and 
 
management of acute myeloid leukemia in adults: recommendations from an 
 
international expert panel, on behalf of European LeukemaiNet. Blood. 2010 Jan 
 
21;115(3):453-74. Epub 2009 Oct 30 
 
2  Attar E, DeAngelo D, Ballen K, Learner E, Trehu E, et al. A Phase I/II, National, 
 
Multicenter, Open Label Study of Bortezomib (Velcade) and Fludarabine, 
 
Cytarabine and Idarubicin (Flag-Ida) (V-Flag-Ida) in Pts with Relapsed and/or 
 
Refractory Acute Myeloblastic Leukemia (AML). Blood (ASH Annual Meeting 
 
Abstracts) 114: 4140.  
3 Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, et al. 
Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer 
Res 1999;59(11):2615-22. 
4 Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J. The proteasome inhibitor PS-341 
in cancer therapy. Clin Cancer Res 1999;5(9):2638-45. 
5 Cusack JC, Jr., Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, et al. Enhanced 
chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for 
systemic nuclear factor-kappaB inhibition. Cancer Res 2001;61(9):3535-40. 
6 LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, et al. 
Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and 
prolongs survival in a murine model. Cancer Res 2002;62(17):4996-5000. 
7 Williams S, Pettaway C, Song R, Papandreou C, Logothetis C, McConkey DJ. Differential 
effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in 
human prostate tumor xenografts. Mol Cancer Ther 2003;2(9):835-43. 
8 Nawrocki ST, Bruns CJ, Harbison MT, Bold RJ, Gotsch BS, Abbruzzese JL, et al. Effects 
of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic 
human pancreatic tumor xenografts. Mol Cancer Ther 2002;1(14):1243-53. 
9 Satou Y, Nosaka K, Koya Y, Yasunaga JI, Toyokuni S, Matsuoka M. Proteasome 
inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both 
in vivo and in vitro. Leukemia 2004;18:1357-63. 
10 Boccadoro M, Morgan G, Cavenagh J. Preclinical evaluation of the proteasome inhibitor 
bortezomib in cancer therapy. Cancer Cell Int 2005;5:18. 
11 Goel A, Dispenzieri A, Geyer SM, Greiner S, Peng KW, Russell SJ. Synergistic activity 
of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP 
skeletally targeted radiotherapy in an orthotopic model of multiple myeloma. Blood 
2006;107(10):4063-70. 


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12 Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, et al. The 
proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to 
conventional 
chemotherapeutic 
agents: 
therapeutic 
applications. 
Blood 
2003;101(6):2377-80. 
13 Sayers TJ, Brooks AD, Koh CY, Ma W, Seki N, Raziuddin A, et al. The proteasome 
inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by 
reducing levels of c-FLIP. Blood 2003;102(1):303-10. 
14 Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S. The proteasome inhibitor 
bortezomib interacts synergistically with histone deacetylase inhibitors to induce 
apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood 
2003;102(10):3765-74. 
15 O'Connor OA, Smith EA, Toner LE, Teruya-Feldstein J, Frankel S, Rolfe M, et al. The 
combination of the proteasome inhibitor bortezomib and the bcl-2 antisense 
molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide. Clin 
Cancer Res. 2006;12(9):2902-11. 
16 David E, Sun SY, Waller EK, Chen J, Khuri FR, Lonial S. The combination of the 
farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib 
induces synergistic apoptosis in human myeloma cells that is associated with down-
regulation of p-AKT. Blood 2005;106(13):4322-9. 
17 McConkey DJ, Pettaway C, Elliott P, Adam J, Papandreou C, Herrmann JL, et al. The 
proteasome as a new drug target in metastatic prostate cancer. In: 7th Annual 
Genitourinary Oncology Conference; 1999 February 1999; Houston, TX. 
18 Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, et al. The 
proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug 
resistance in human multiple myeloma cells. Cancer Res 2001;61(7):3071-6. 
19 Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH. Proteasome 
inhibitors induce a terminal unfolded protein response in multiple myeloma cells. 
Blood 2006;107(12):4907-16. 
20 Ling YH, Liebes L, Ng B, Buckley M, Elliott PJ, Adams J, et al. PS-341, a novel 
proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association 
with G2-M phase arrest and apoptosis. Mol Cancer Ther 2002;1(10):841-9. 
21 Yang Y, Ikezoe T, Saito T, Kobayashi M, Koeffler HP, Taguchi H. Proteasome inhibitor 
PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells via 
the JNK/c-Jun/AP-1 signaling. Cancer Sci 2004;95(2):176-80. 
22 Kaluz S, Kaluzova M, Stanbridge EJ. Proteasomal inhibition attenuates transcriptional 
activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha 
C-terminal activation domain. Mol Cell Biol 2006;26(15):5895-907. 


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23 An WG, Hwang SG, Trepel JB, Blagosklonny MV. Protease inhibitor-induced apoptosis: 
accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are 
independent markers of proteasome inhibition. Leukemia 2000;14(7):1276-83. 
24 Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, et al. Bortezomib 
mediates antiangiogenesis in multiple myeloma via direct and indirect effects on 
endothelial cells. Cancer Res 2006;66(1):184-91. 
25 Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, et al. Molecular 
sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad 
Sci U S A 2002;99(22):14374-9. 
26 Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ. Proteasome 
inhibition measurements: clinical application. Clin Chem 2000;46(5):673-83. 
27 Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman 
G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng 
H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous versus 
intravenous administration of bortezomib in patients with relapsed multiple 
myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 
May;12(5):431-40. 
28 Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase 
I Trial of the Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic 
Malignancies. J Clin Oncol 2002;20(22):4420-7. 
29 Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase 
I Trial of the Proteasome Inhibitor PS-341 in Patients with Refractory Hematologic 
Malignancies. J Clin Oncol 2002;20(22):4420-7. 
30 Aghajanian C, Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ, et al. A Phase I Trial 
of the Novel Proteasome Inhibitor PS341 in Advanced Solid Tumor Malignancies. 
Clin Cancer Res 2002;8(8):2505-11. 
31 Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, et al. Phase I trial of 
the proteasome inhibitor bortezomib in patients with advanced solid tumors with 
observations 
in 
androgen-independent 
prostate 
cancer. 
J 
Clin 
Oncol 
2004;22(11):2108-21. 
32 Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Castritis E, Bitsaktsis A, Pangalis 
GA. Treatment of relapsed or refractory Waldenström's macroglobulinemia with 
bortezomib. Haematologic. 2005;90(12):1655-8. 
33 Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, et al. A phase 2 
study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 
2004;127(2):165-72. 


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34 Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A Phase 2 
Study of Bortezomib in Relapsed, Refractory Myeloma. N Engl J Med 
2003;348(26):2609-17. 
35 Bladé J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, et al. Criteria for 
evaluating disease response and progression in patients with multiple myeloma 
treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma 
Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br 
J Haematol 1998;102(5):1115-23. 
36 Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. 
Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma. N Engl J 
Med 2005;352(24):2487-98. 
37 Richardson P, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, et al. 
Bortezomib Continues Demonstrates Superior Efficacy Compared with High-Dose 
Dexamethasone in Relapsed Multiple Myeloma: Updated Results of the APEX Trail. 
Blood 2005;106(11):Abstract 2547. 
38 Fisher R, Bernstein S, Kahl B, Djulbegovic B, Robertson M, de Vos S, et al. Multicenter 
Phase II Study of Bortezomib in Patients With Relapsed or Refractory Mantle Cell 
Lymphoma. J Clin Oncol 2006;24(30):4867-74. 
39 Goy A, Bernstein S, Kahl B, Djulbegovic B, Robertson M, Vos S, et al. Durable 
Responses with Bortezomib in Patients with Relapsed or Refractory mantle Cell 
Lymphoma:  Updated Time-to-Event Analyses of the Multicenter PINNACLE 
Study. Blood 2007;110:Abstract 125. 
40 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. 
Bortezomib plus melphalan and prednisone for initial treatment of multiple 
myeloma. N Engl J Med 2008;359(9):906-17. 
41 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. 
Bortezomib plus melphalan and prednisone for initial treatment of multiple 
myeloma. N Engl J Med 2008;359(9):906-17. 
42 Mateos M-V, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, 
et al. Bortezomib plus melphalan-prednisone continues to demonstrate a survival 
benefit vs melphalan-prednisone in the phase III VISTA trial in previously untreated 
multiple myeloma after 3 years' follow-up and extensive subsequent therapy use. 
Blood 2009;114:Abstract 3859. 
43 Gordon AN, Tonda M, Sun S, Rackoff W. Long-term survival advantage for women 
 
treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 
 
randomized study of recurrent and refractory epithelial ovarian cancer. Gynecologic 
 
Oncology. 2004; 95(1):1–8. 
 


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44 Gordon AN, Fleagle JT, Guthrie D, et al. Recurrent epithelial ovarian carcinoma: a 
 
randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J 
 
Clin Oncol; 2001; 19(14): 3312-22. 
 
45 Muggia FM, Hainsworth JD, Jeffers S, Miller P, Groshen S, Tan M, et al. Phase II study 
 
of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity 
 
modification by liposomal encapsulation. J Clin Oncol. 1997;15(3):987. 
 
46 Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, et al. Recurrent epithelial 
 
ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin 
 
versus topotecan. J Clin Oncol. 2001;19(14):3312. 
 
47 O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, et al. Reduced cardiotoxicity and 
 
comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl 
 
(CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of 
 
metastatic breast cancer. Ann Oncol. 2004;15(3):440. 
 
48  Northfelt DW, Dezube BJ, Thommes JA, Miller BJ, Fischl MA, et al. Pegylated-
 
liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the 
 
treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III 
 
clinical trial. J Clin Oncol. 1998;16(7):2445. 
 
49 Stewart S, Jablonowski H, Goebel FD, Arasteh K, Spittle M, et al. Randomized 
 
comparative trial of pegylated liposomal doxorubicin versus bleomycin and 
 
vincristine in the treatment of AIDS-related Kaposi's sarcoma. International 
 
Pegylated Liposomal Doxorubicin Study Group. J Clin Oncol. 1998;16(2):683. 
 
50 Orlowski RZ, Nagler A, Sonneveld P, BladéJ, Hajek R, et al. Randomized phase III study 
 
of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib 
 
alone in relapsed or refractory multiple myeloma: combination therapy improves 
 
time to progression. J Clin Oncol. 2007;25(25):3892. 
 
51  Attar E, DeAngelo D, Ballen K, Learner E, Trehu E, et al. A Phase I/II, National, 
 
Multicenter, Open Label Study of Bortezomib (Velcade) and Fludarabine, 
 
Cytarabine and Idarubicin (Flag-Ida) (V-Flag-Ida) in Pts with Relapsed and/or 
 
Refractory Acute Myeloblastic Leukemia (AML). Blood (ASH Annual Meeting 
 
Abstracts) 114: 4140.  
 
52  Tomlinson B, Tuscano T, Abedi M, Welborn J, O’Donnell R, Arora M, Verman R, 
Jones K, Jonas BA. Phase II trial of the combination of subcutaneous bortezomib 
(Bortez) and pegylated liposomal doxorubicin (PLD) for the treatment of patients 
with acute myelogenous leukemia (AML). J Clin Oncol, 33(15suppl): 7081. 
 
53  Cashen AF, Schiller GJ, O'Donnell MR, DiPersio JF. Multicenter, phase II study of 
decitabine for the first-line treatment of older patients with acute myeloid leukemia. J 
Clin Oncol. 2010;28(4):556-61. 


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54 Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, Gau 
JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, 
Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, 
phase III trial of decitabine versus patient choice, with physician advice, of either 
supportive care or low-dose cytarabine for the treatment of older patients with newly 
diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30(21):2670-7. 
 
55  Ettou S, Humbrecht C, Benet B, Billot K, d'Allard D, Mariot V, Goodhardt M, Kosmider 
O, Mayeux P, Solary E, Fontenay M. Epigenetic control of NF-kappaB-dependent 
FAS gene transcription during progression of myelodysplastic syndromes. Molecular 
cancer research : MCR. 2013;11(7):724-35. 
 
56  Breccia M, Alimena G. NF-kappaB as a potential therapeutic target in myelodysplastic 
syndromes 
and 
acute 
myeloid 
leukemia. 
Expert 
Opin 
Ther 
Targets. 
2010;14(11):1157-76. 
 
57  Fabre C, Grosjean J, Tailler M, Boehrer S, Ades L, Perfettini JL, de Botton S, Fenaux P, 
Kroemer G. A novel effect of DNA methyltransferase and histone deacetylase 
inhibitors: NFkappaB inhibition in malignant myeloblasts. Cell cycle (Georgetown, 
Tex). 2008;7(14):2139-45. 
 
58  Khong T, Sharkey J, Spencer A. The effect of azacitidine on interleukin-6 signaling and 
nuclear factor-kappaB activation and its in vitro and in vivo activity against multiple 
myeloma. Haematologica. 2008;93(6):860-9. 
 
59  Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, 
Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, 
Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, 
Marcucci G. Clinical response and miR-29b predictive significance in older AML 
patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 
2010;107(16):7473-8. 
 
60  Bhatnagar B, Duong VH, Gourdin TS, Tidwell ML, Chen C, Ning Y, Emadi A, 
Sausville EA, Baer MR. Ten-day decitabine as initial therapy for newly diagnosed 
patients with acute myeloid leukemia unfit for intensive chemotherapy. Leuk 
Lymphoma. 2014;55(7):1533-7. 
 
61  Ritchie EK, Feldman EJ, Christos PJ, Rohan SD, Lagassa CB, Ippoliti C, Scandura JM, 
Carlson K, Roboz GJ. Decitabine in patients with newly diagnosed and relapsed 
acute myeloid leukemia. Leuk Lymphoma. 2013;54(9):2003-7 
 
 
 
 
 


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62  Blum W, Schwind S, Tarighat SS, Geyer S, Eisfeld AK, Whitman S, Walker A, Klisovic 
R, Byrd JC, Santhanam R, Wang H, Curfman JP, Devine SM, Jacob S, Garr C, 
Kefauver C, Perrotti D, Chan KK, Bloomfield CD, Caligiuri MA, Grever MR, 
Garzon R, Marcucci G. Clinical and pharmacodynamic activity of bortezomib and 
decitabine in acute myeloid leukemia. Blood. 2012;119(25):6025-31. 
 


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8.    
APPENDICES  
8.1    Study Calendar/Toxicity and Events  
 
INDUCTION: Each cycle except as indicated 
(Absent allowed delays, cycles repeat every 28 days up to 4 cycles.)* 
Post-Induction: Each cycle except as 
indicated (Absent allowed delays, 
cycles repeat every 28 days up to 12 
cycles.)* 
 
   
Pre-
Study 
(≤14 
days) 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D12 
D15 
Prior to 
next 
cyclej 
D1-5 
D8 
D12 
D22 
Prior 
to 
next 
cyclej 
Off 
Study 
F/U  
until 
Relapse 
 
Doxil/LipoDox (Do) 
 
 
 
 
 
 
 
 
 
 
 
Do 
 
 
 
 
Do 
 
 
 
 
Bortezomib (B) 
 
 
 
 
 
B 
 
 
B 
 
 
B 
B 
 
B (D1) 
B 
 
 
 
 
 
Decitabine 
 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
 
 
 
D 
(D1-5) 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
Xa 
X 
Xa 
 
 
 
X 
X 
X 
Vital signs 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
Performance status 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
Xa 
X 
Xa 
 
 
 
X 
X 
X 
CBC w/diff 
X 
X a 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Xa 
 
 
 
X 
X 
X 
Serum chemistry b 
X 
X a,c 
 
 
 
X c 
 
 
X c 
 
 
X c 
X c 
X 
Xa,c 
 
 
 
Xc 
X 
X 
EKGd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
 
 
 
 
Xd 
X 
 
MUGA or ECHO e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
 
 
Xe 
X 
 
Adverse event evaluation 
X 
X---------------------------------------------------------------------------------X 
 
X 
X-----------------------X 
 
 
 
Neurologic evaluationf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
Bone Marrow Biopsyg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
Xg 
Xg 
X 
B-HCGh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prophylaxisi 
 
Xi 
 
 
 
 
 
 
 
 
 
 
 
Xi 
Xi 
 
 
 
Xi 
 
 


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* Variations of ± 3 days of the scheduled visit are permitted.   
a. Pre-treatment/pre-cycle studies need to be repeated in week 1 only if the patient’s condition is deteriorating. 
b. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium. 
c. Induction cycles only; chemistries weekly in addition to day 5, 12 and 15. For post-induction cycles, chemistries should be done prior to each new course and 
every two weeks, unless monitoring for prior AE resolution.  
d. EKG to be done at baseline, after each induction cycle, after every 3 cycles of post-induction therapy, at the end of study, and as clinically indicated. 
e. MUGA or ECHO to be done at screening (within 30 days prior to start of study medication), every two cycles starting with Cycle 7 [e.g. pre-Cycle 7, 9, 11 
(note: induction and post-induction cycles are added together to determine cycle number)], and End of Study Treatment, and as clinically indicated. During 
treatment with pegylated liposomal doxorubicin, when a patient has reached a total (lifetime cumulative) anthracycline dose of 300 mg/m2, follow-up MUGA 
scans or 2-D echocardiograms are to be performed every two cycles (and this schedule will replace the schedule of assessments every two cycles after Cycle 6 
listed above for applicable patients). 
f. Includes a motor exam, reflex exam, sensory exam and administration of the Neurotoxicity Assessment Tool. 
g. Bone Marrow Bx/Aspirate done at baseline, after each induction cycle until CR, then every after every 6 cycles of post-induction therapy or with signs of 
relapse or as clinically indicated. Send for morphology (pathology), flow cytometry, cytogenetics.  Also send for molecular studies if indicated. 
h. Serum pregnancy test (women of childbearing potential). 
i. Acyclovir prophylaxis  will begin before cycle #1 and continue throughout treatment and for 6 months after completion 
j. Repeats every 28 days, or up to every 42 days if awaiting resolution of Grade 3 or 4 AE’s 
k. Pegylated liposomal doxorubicin should be discontinued once a patient reaches a lifetime cumulative dose of 550mg/m2 doxorubicin (prior non-doxorubicin 
included in this value using published conversion factors). The patient may continue on post-induction therapy with decitabine and bortezomib. 
 


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8.2 Karnofsky Performance Status Scale 
The following table presents the Karnofsky performance status scale. 
Points 
Description 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or to do active work 
60 
Requires occasional assistance but is able to care for most of his/her needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization indicated.  Death not imminent 
20 
Very sick; hospitalization necessary; active support treatment necessary 
10 
Moribund; fatal processes progressing rapidly 
0 
Dead 
Sources:  Mor V, Laliberte L, Morris JN, Wiemann M.  The Karnofsky Performance Status 
Scale:  an examination of its reliability and validity in a research setting.  Cancer 
1984;53:2002-2007. 
Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the 
palliative treatment of cancer. Cancer1948; 1(4):634-656. 
Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: 
MacLeod CM, ed. Evaluation of Chemotherapeutic Agents. New York: Columbia University 
Press, 1949, I9 1-205. 
 
 


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8.3    Body Surface Area  
Body surface area (BSA) should be calculated using a standard nomogram that yields the 
following results in meters squared (m2): 
BSA = 
3131
)
(
)
(
lbs
Wt
inches
Ht
×
 
or 
BSA = 
3600
)
(
)
(
kg
Wt
cm
Ht
×
 
 
 


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


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8.5    Common Terminology Criteria for Adverse Events  
http://ctep.cancer.gov/reporting/ctc.html 


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8.6    RTOG/EORTC Late Radiation Morbidity Scoring Scheme  
http://www.rtog.org/members/protocols/0211/app3.html 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme 
Use for toxicity occurring greater than 90 days after radiation therapy. 
Toxicity 
Grade 
0 
1 
2 
3 
4 
Bladder- 
Late RT 
Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Slight 
epithelial 
atrophy/mino
r 
telangiectasi
a 
(microscopic 
hematuria) 
Moderate 
frequency / 
generalized 
telangiectasi
a / 
intermittent 
macroscopic 
hematuria 
Severe 
frequency 
and 
dysuria/sever
e generalized 
telangiectasi
a (often with 
petechiae); 
frequent 
hematuria; 
reduction in 
bladder 
capacity 
(<150 cc) 
Necrosis/contract
ed bladder 
(capacity <100 cc) 
/ severe 
hemorrhagic 
cystitis 
Bone- Late 
RT Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Asymptomati
c; no growth 
retardation; 
reduced 
bone density 
Moderate 
pain or 
tenderness; 
growth 
retardation; 
irregular 
bone 
sclerosis 
Severe pain 
or 
tenderness; 
complete 
arrest of 
bone growth; 
dense bone 
sclerosis 
Necrosis/ 
spontaneous 
fracture 
Brain- Late 
RT Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Mild 
headache; 
slight 
lethargy 
Moderate 
headache; 
great 
lethargy 
Severe 
headaches; 
severe CNS 
dysfunction 
(partial loss 
of power or 
dyskinesia) 
Seizures or 
paralysis; coma 
Esophagus- 
Late RT 
Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Mild fibrosis; 
slight 
difficulty in 
swallowing 
solids; no 
pain on 
swallowing 
Unable to 
take solid 
food 
normally; 
swallowing 
semi-solid 
food; 
dilatation 
may be 
indicated 
Severe 
fibrosis; able 
to swallow 
only liquids; 
may have 
pain on 
swallowing; 
dilation 
required 
Necrosis /  
perforation; fistula 


University of California Davis 
 
VELCADE® (bortezomib) for Injection 
Clinical Study Protocol [UCDCC#230] 
 
Version Date:   04/03/17 
 
 
Toxicity 
Grade 
0 
1 
2 
3 
4 
Heart- Late 
RT Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Asymptomati
c or mild 
symptoms; 
transient T 
wave 
inversion and 
ST changes; 
sinus 
tachycardia 
>110 (at rest) 
Moderate 
angina on 
effort; mild 
pericarditis; 
normal heart 
size; 
persistent 
abnormal T 
wave and ST 
changes; low 
QRS 
Severe 
angina; 
pericardial 
effusion; 
constrictive 
pericarditis; 
moderate 
heart failure; 
cardiac 
enlargement; 
EKG 
abnormalities 
Tamponade / 
severe heart 
failure/severe 
constrictive 
pericarditis 
Joint- Late 
RT Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Mild joint 
stiffness; 
slight 
limitation of 
movement 
Moderate 
stiffness; 
intermittent 
or moderate 
joint pain; 
moderate 
limitation of 
movement 
Severe joint 
stiffness; 
pain with 
severe 
limitation of 
movement 
Necrosis / 
complete fixation 
Kidney- Late 
RT Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Transient 
albuminuria; 
no 
hypertension; 
mild 
impairment of 
renal 
function; urea 
25-35 mg%; 
creatinine 
1.5-2.0 mg%; 
creatinine 
clearance 
>75% 
Persistent 
moderate 
albuminuria 
(2+); mild 
hypertension
; no related 
anemia; 
moderate 
impairment 
of renal 
function; 
urea >36–
60 mg%; 
creatinine 
clearance 
>50-74% 
Severe 
albuminuria; 
severe 
hypertension; 
persistent 
anemia 
(<10 g%); 
severe renal 
failure; urea 
>60 mg%; 
creatinine >4 
mg%; 
creatinine 
clearance  
<50% 
Malignant 
hypertension; 
uremic coma / 
urea >100% 
Larynx- Late 
RT Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Hoarseness; 
slight 
arytenoid 
edema 
Moderate 
arytenoid 
edema; 
chondritis 
Severe 
edema; 
severe 
chondritis 
Necrosis 


University of California Davis 
 
VELCADE® (bortezomib) for Injection 
Clinical Study Protocol [UCDCC#230] 
 
Version Date:   04/03/17 
 
 
Toxicity 
Grade 
0 
1 
2 
3 
4 
Liver- Late 
RT Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Mild 
lassitude; 
nausea; 
dyspepsia; 
slightly 
abnormal 
liver function 
Moderate 
symptoms; 
some 
abnormal 
liver function 
tests; serum 
albumin 
normal 
Disabling 
hepatic 
insufficiency; 
liver function 
tests grossly 
abnormal; 
low albumin; 
edema or 
ascites 
Necrosis / hepatic 
coma or en-
cephalopathy 
Lung- Late 
RT Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Asymptomati
c or mild 
symptoms 
(dry cough); 
slight 
radiographic 
appearances 
Moderate 
symptomatic 
fibrosis or 
pneumonitis 
(severe 
cough); low 
grade fever; 
patchy 
radiographic 
appearances 
Severe 
symptomatic 
fibrosis or 
pneumonitis; 
dense 
radiographic 
changes 
Severe respiratory 
insufficiency / 
continuous O2 / 
assisted 
ventilation 
Mucous 
membrane- 
Late RT 
Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Slight 
atrophy and 
dryness 
Moderate 
atrophy and 
telangiectasi
a; little 
mucus 
Marked 
atrophy with 
complete 
dryness; 
severe 
telangiectasi
a 
Ulceration 
Salivary 
glands- 
Late RT 
Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Slight 
dryness of 
mouth; good 
response on 
stimulation 
Moderate 
dryness of 
mouth; poor 
response on 
stimulation 
Complete 
dryness of 
mouth; no 
response on 
stimulation 
Fibrosis 
Skin- Late 
RT Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Slight 
atrophy; 
pigmentation 
change; 
some hair 
loss 
Patchy 
atrophy; 
moderate 
telangiectasi
a; total hair 
loss 
Marked 
atrophy; 
gross 
telangiectasi
a 
Ulceration 


University of California Davis 
 
VELCADE® (bortezomib) for Injection 
Clinical Study Protocol [UCDCC#230] 
 
Version Date:   04/03/17 
 
 
Toxicity 
Grade 
0 
1 
2 
3 
4 
Small/Large 
intestine- 
Late RT 
Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Mild diarrhea; 
mild 
cramping; 
bowel 
movement 5 
x daily slight 
rectal 
discharge or 
bleeding 
Moderate 
diarrhea and 
colic; bowel 
movement 
>5 x daily; 
excessive 
rectal mucus 
or 
intermittent 
bleeding 
Obstruction 
or bleeding, 
requiring 
surgery 
Necrosis / 
perforation fistula 
Spinal cord- 
Late RT 
Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Mild 
Lhermitte’s 
syndrome 
Severe 
Lhermitte’s 
syndrome 
Objective 
neurological 
findings at or 
below cord 
level 
treatment 
Mono-, para-, 
quadriplegia 
Subcutaneou
s tissue- 
Late RT 
Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Slight 
induration 
(fibrosis) and 
loss of 
subcutaneou
s fat 
Moderate 
fibrosis but 
asymptomati
c; slight field 
contracture; 
<10% linear 
reduction 
Severe 
induration 
and loss of 
subcutaneou
s tissue; field 
contracture 
>10% linear 
measuremen
t 
Necrosis 
Eye- Late RT 
Morbidity 
Scoring 
No 
change 
from 
baselin
e 
Asymptomati
c cataract; 
minor corneal 
ulceration or 
keratitis 
Symptomatic 
cataract; 
moderate 
corneal 
ulceration; 
minor 
retinopathy 
or glaucoma 
Severe 
keratitis; 
severe 
retinopathy 
or 
detachment; 
severe 
glaucoma 
Panophthal-mitis; 
blindness 
Radiation-
Other 
(Specify, 
__________) 
None 
Mild 
Moderate 
Severe 
Life-threatening or 
disabling 
 
 
 


University of California Davis 
 
VELCADE® (bortezomib) for Injection 
Clinical Study Protocol [UCDCC#230] 
 
Version Date:   04/03/17 
 
 
    
Neurotoxicity Assessment Tool 
 
 


University of California Davis 
 
VELCADE® (bortezomib) for Injection 
Clinical Study Protocol [UCDCC#230] 
 
Version Date:   04/03/17 
 
 
8.7    Package Insert for Doxil 
 
http://www.doxil.com/assets/DOXIL_PI_Booklet.pdf 
 
 
 


University of California Davis 
 
VELCADE® (bortezomib) for Injection 
Clinical Study Protocol [UCDCC#230] 
 
Version Date:   04/03/17 
 
 
 
8.8  Package Insert for LipoDox 
http://www.caraco.com/Lipodox/Lipodox-50%20injection-outsert.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


University of California Davis 
 
VELCADE® (bortezomib) for Injection 
Clinical Study Protocol [UCDCC#230] 
 
Version Date:   04/03/17 
 
 
8.9  Package Insert for Decitabine 
http://otsuka-us.com/products/Documents/DACOGEN.PI.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


University of California Davis 
 
VELCADE® (bortezomib) for Injection 
Clinical Study Protocol [UCDCC#230] 
 
Version Date:   04/03/17 
 
 
8.11 
Data Submission Schedule 
 
Electronic versions of the eligibility checklist and case report forms will be sent to 
participating sites upon request.  
All data will be collected using UC Davis data collection forms. Copies of the completed 
forms will be submitted to UC Davis data coordinating center for data entry and storage in a 
secure location. The original data collection forms will reside at the originating institution in 
secure location.  
 
 
 SUBMIT WITHIN 24 HOURS OF REGISTRATION:  
Patient Registration Form  
 
 SUBMIT WITHIN 14 DAYS OF REGISTRATION:  
In‐House Pre‐Study Evaluation Form (IH‐102)  
 
 SUBMIT WITHIN 7 DAYS OF SCREENING FAILURE:  
Patient Screen Failure Form (IH‐103)  
 
 SUBMIT WITH 14 DAYS OF CYCLE COMPLETION:  
In‐House Adverse Event/Drug Relationship Form  
 
 
 SUBMIT WITHIN 14 DAYS OF END OF EACH TREATMENT CYCLE:  
In‐House Treatment Cycle Form (IH‐201)  
 
 SUBMIT WITHIN 14 DAYS OF EACH RESPONSE ASSESSMENT:  
Tumor Measurement Log  
 
 SUBMIT WITHIN 14 DAYS OF OFF TREATMENT:  
End of Treatment/Expiration Form (IH‐301)  
 
 SUBMIT WITHIN 14 DAYS OF KNOWLEDGE OF DEATH IF PATIENT IS STILL 
ON STUDY OR 30–DAYS IF OFF STUDY:  
End of Treatment/Expiration Form (IH‐301)  
 
 SUBMIT WITHIN 2 DAYS OF KNOWLEDGE OF PROTOCOL DEVIATION:  
Clinical Trials Support Unit: Notice of Protocol Deviation  
 
 SUBMIT WITHIN 14 DAYS OF EACH REQUIRED FOLLOW‐UP ENCOUNTER:  
Follow‐Up Form (IH‐302)  
 
 ALL SERIOUS ADVERSE EVENTS MUST BE REPORTED AS OUTLINED IN THE 
PROTOCOL 
 
 
 
 
 


University of California Davis 
 
VELCADE® (bortezomib) for Injection 
Clinical Study Protocol [UCDCC#230] 
 
Version Date:   04/03/17 
 
 
8.12 Pregnancy Form