Clinical trial NCT01453088
Conditions: Multiple Myeloma
Keywords: multiple myeloma transplant
Sponsor: Hackensack Meridian Health
Start date: 2010-06-24; Completion date: 2022-05-01
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this study the investigators are comparing this standard regimen to the newly established regimen of melphalan and bortezomib.

Detailed description:
In this study the investigators are comparing this standard regimen to the newly established regimen of melphalan and bortezomib.

Conditioning Regimens:

Treatment arm A Melphalan is administered at a dose of 200mg/m2 by rapid intravenous infusion via a central or peripheral vein over 30 minutes to one hour.

Melphalan will be given as a single dose (not split over 2 or more days) and given on day-1.

Dosing will be based on body surface area calculated using actual body weight

Stem cell infusion:

Stem cell infusion will occur on day 0 and will be at least 20 hours after the infusion of melphalan. The infusion of peripheral blood stem cells will be done in accordance with the Blood and Marrow Transplant program standard operating procedures.

Filgrastim will be administered at a dose of 5 mcg/kg (rounded to vial size) every other day starting on day+3 then daily starting on day 9 until engraftment (at least).

Treatment arm B

Bortezomib:

Bortezomib is administered by rapid I.V. push (over 3-5 seconds) via a central or peripheral vein into a flowing saline line. Bortezomib will be administered any time on day -4 and at least 20 hrs after the start of the melphalan infusion on day -1.

Dosing will be based on actual body weight. Dexamethasone is administered at a dose of 20 mg IV prior to each bortezomib infusion.

Melphalan:

Melphalan is administered at a dose of 200mg/m2 by rapid intravenous infusion via a central or peripheral vein over 30 minutes to one hour.

Melphalan will be given as a single dose (not split over 2 or more days) and given of day-2.

Dosing will be based body surface area calculated using actual body weight

Stem cell infusion:

Stem cell infusion will occur on day 0 and will be at least 18 hours after the infusion of the bortezomib. The infusion of peripheral blood stem cells will be done in accordance with the Blood and Marrow Transplant program standard operating procedures.

Filgrastim will be administered at a dose of 5 mcg/kg (rounded to vial size) every other day starting on day+3 then daily starting on day 9 until engraftment (at least).

Post-transplant Supportive Care will be administered in accordance to the Blood and Marrow Transplant program standard operating procedures.

Arms: arm 1: Melphalan is administered at a dose of 200mg/m2 by rapid intravenous infusion via a central or peripheral vein over 30 minutes to one hour.

Melphalan will be given as a single dose (not split over 2 or more days) and given on day-1.

Dosing will be based on body surface area calculated using actual body weight

Stem cell infusion:

Stem cell infusion will occur on day 0 and will be at least 20 hours after the infusion of melphalan. The infusion of peripheral blood stem cells will be done in accordance with the Blood and Marrow Transplant program standard operating procedures.

Filgrastim will be administered at a dose of 5 mcg/kg (rounded to vial size) every other day starting on day+3 then daily starting on day 9 until engraftment (at least). arm 2: Bortezomib:

Bortezomib is administered by rapid I.V. push (over 3-5 seconds) via a central or peripheral vein into a flowing saline line. Bortezomib will be administered any time on day -4 and at least 20 hrs after the start of the melphalan infusion on day -1.
Interventions: intervention 1: Melphalan intervention 2: Bortezomib
Intervention descriptions: intervention 1: Melphalan is administered at a dose of 200mg/m2 by rapid intravenous infusion via a central or peripheral vein over 30 minutes to one hour.

Melphalan will be given as a single dose (not split over 2 or more days) and given on day-1.

Dosing will be based on body surface area calculated using actual body weight

Stem cell infusion:

Stem cell infusion will occur on day 0 and will be at least 20 hours after the infusion of melphalan. The infusion of peripheral blood stem cells will be done in accordance with the Blood and Marrow Transplant program standard operating procedures.

Filgrastim will be administered at a dose of 5 mcg/kg (rounded to vial size) every other day starting on day+3 then daily starting on day 9 until engraftment (at least). intervention 2: Bortezomib:

Bortezomib is administered by rapid I.V. push (over 3-5 seconds) via a central or peripheral vein into a flowing saline line. Bortezomib will be administered any time on day -4 and at least 20 hrs after the start of the melphalan infusion on day -1.

Protocol documents:
Prot_SAP_000.pdf: 
Pro00001307 Protocol, Amendment 12 – 08Nov2019  
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HackensackUMC IRB Protocol # Pro00001307 
 
Phase III Randomized Study of Autologous Stem Cell Transplantation with 
High-Dose Melphalan Versus High-Dose Melphalan and Bortezomib in 
Patients with Multiple Myeloma 60 Years or Older 
 
Protocol Version 
Date of Protocol 
Original Version
25Feb2010
Amendment 1
03Aug2010
Amendment 2
02Nov2010
Amendment 3
07Feb2011
Amendment 4
17Feb2012
Amendment 5
04Jun2012
Amendment 6
14Sep2012
Amendment 7
23May2013
Amendment 8
05Sep2013
Amendment 9                    
19Jun2014
Amendment 10
06Jan2016
Amendment 11
12Dec2016
Amendment 12
08Nov2019
 
 
BLOOD AND MARROW TRANSPLANTATION PROGRAM 
HACKENSACK UNIVERSITY MEDICAL CENTER 
 
Georgetown University Medical Center 
 
 
Principle Investigator: 
Michele Donato, MD (551) 996-5900 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION AND STUDY RATIONALE ............................................................. 6 
1.1 
Overview of the Disease ........................................................................................ 6 
1.2 
Melphalan ............................................................................................................ ..8 
1.3 
VELCADE (bortezomib) for Injection ................................................................ 10 
1.4 
Combination of Bortezomib and Other Agents…………………………………14 
2 
STUDY OBJECTIVE…………………………………………………………………..17 
2.1 
Primary Objective ................................................................................................ 17 
2.2 
Secondary Objectives........................................................................................... 17 
3 
INVESTIGATIONAL PLAN .......................................................................................... 18 
3.1 
Overall Design and Plan of Study ........................................................................ 18 
3.2 
Patient Selection................................................................................................... 18 
3.3 
Inclusion Criteria ................................................................................................. 18 
3.4 
Exclusion Criteria ................................................................................................ 18 
3.5 
Patient Evaluations............................................................................................... 20 
3.6 
Analysis of PBSC and Marrow Components....................................................... 20 
3.7 
Post-Transplant Evaluation .................................................................................. 20 
3.8 
Post-Transplant re-staging of disease .................................................................. 21 
3.9 
Study Treatments ................................................................................................. 21 
3.10 
Outline of Treatment Plan .................................................................................... 24 
3.11 
Conditioning Regiments ...................................................................................... 24 
3.12 
Stem Cell Infusion ............................................................................................... 25 
3.13 
Post-transplant Cytokine Administration ............................................................. 25 
3.14 
Post-transplant Supportive Care .......................................................................... 26 
3.15 
Disease Response ................................................................................................. 26 
3.16 
Dosing of Agents ................................................................................................. 26 
3.17 
Pre-Transplant Therapy ....................................................................................... 28 
3.18 
Treatment Assignment ......................................................................................... 28 
3.19 
Blinding, Packaging, and Labeling ...................................................................... 28 
3.20 
Concomitant Treatment ....................................................................................... 28 
3.21 
Treatment Compliance ......................................................................................... 28 
3.22 
Duration of Treatment and Patient Participation ................................................. 29 
3.23 
Termination of Treatment and/or Study Participation ......................................... 29 
4 
ADVERSE EVENTS ....................................................................................................... 30 
4.1 
Definitions............................................................................................................ 30 
4.2 
Procedures for AE and SAE Reporting ............................................................... 31 
4.3 
Assessment of Toxicity (Appendix B) ................................................................. 31 
5 
STATISTICAL EVALUATION ..................................................................................... 33 
5.1 
Primary Objective ................................................................................................ 33 
5.2 
Secondary Objectives........................................................................................... 33 
5.3 
Accrual, Registration & Follow-Up…………………………………………….33 
5.4 
Sample Size and Power Calculations ................................................................... 34 
5.5 
Efficacy Analysis  ................................................................................................ 34 
5.6 
Statistical Hyopthesis ........................................................................................... 34 
5.7       Primary Endpoints ............................................................................................... 35 
5.8 
Secondary Endpoints ……………..…………………………………………….36 


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5.9 
Stopping Rules ..................................................................................................... 38 
5.10 
Monitoring Compliance  ...................................................................................... 38 
5.11 
Data Management and analysis ........................................................................... 38 
6 
ADMINISTRATIVE REQUIREMENTS ....................................................................... 39 
6.1 
Good Clinical Practice ......................................................................................... 39 
6.2 
Ethical Considerations ......................................................................................... 39 
6.3 
Patient Information and Informed Consent.......................................................... 39 
6.4 
Protocol Registration ........................................................................................... 39 
6.5 
Patient Confidentiality ......................................................................................... 39 
6.6 
Record Retention ................................................................................................. 40 
6.7 
Investigational New Drug Excemption ................................................................ 40 
7 
KARNOFSKY PERFORMANCE STATUS SCALE ..................................................... 41 
8 
BODY SURFACE AREA AND CREATININE CLEARANCE 
CALCULATIONS ........................................................................................................... 42 
9 
NYHA CLASSIFICATION OF CARDIAC DISEASE .................................................. 43 
10 
DECLARATION OF HELSINKI.................................................................................... 44 
11 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ......................... 48 
12        REFERENCES ................................................................................................................ 49 
 
 
 
  


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ABBREVIATION LIST 
 
Abbreviation 
 
 
Definition 
C 
degrees Celsius 
M 
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 
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DNA 
deoxyribonucleic acid 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
ht 
Height 
IB 
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 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
IB 
I kappa B alpha-associated protein kinase 
kg 
Kilogram 
Ki 
inhibitory constant 
lbs 
Pounds 
m2 
square meters 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 


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ABBREVIATION LIST 
 
Abbreviation 
 
 
Definition 
mm3 
cubic millimeters 
mmol 
Millimole 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NF-B 
nuclear factor-B 
ng 
Nanogram 
nM 
Nanomole 
p21 
p21(ras) farnesyl-protein transferase 
p27 
cyclin-dependent kinase inhibitor 
p53 
tumor suppressor protein with molecular weight of 53 kDa 
SAE 
serious adverse event 
US 
United States 
USP 
United States Pharmacopeia 
VCAM-1 
vascular cell adhesion molecule 1 
w/w 
weight-to-weight ratio 
wt 
Weight 


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1 
INTRODUCTION AND STUDY RATIONALE 
1.1 
Overview of the Disease 
Multiple myeloma is the second most common hematological malignancy, affecting about 55,000 
Americans.  Limited control of disease can be achieved with conventional dose chemotherapy but 
randomized studies reported improved response rates for patients who are treated with dose-
intense therapy and autologous hematopoietic stem cell (HSC) transplantation.  However, most 
patients who undergo dose-intense therapy will require salvage therapy at a median of two to three 
years after transplantation.  High-dose melphalan (200 mg/m2) appears to be the most effective 
conditioning regimen but the potentially greater tumor cell kill of dose-intense melphalan in 
synergistic combination with other drugs is only now being studied.   
1.1.1 
Multiple Myeloma 
Multiple myeloma is a malignancy of plasma cells and belongs in a family of diseases 
known as plasma cell dyscrasias.   It accounts for about 1% of all cancers and 10% of all 
hematological malignancies.  Thus, it is the second most common “blood cancer,” affecting 
approximately 55,000 Americans. The annual incidence is about 20,000 cases; the annual 
death rate is about 11,000.  The median age at diagnosis is 70 years old.  The disease is 
more common in males (1.3 to 1) and the frequency doubles in African-Americans 
compared to Caucasians. 
1.1.2 
Clinical Studies of High-Dose Therapy of Multiple Myeloma 
Standard dose therapy for most plasma cell disorders includes regimens such as low-dose 
melphalan (32 mg/m2/month) with prednisone.  For patients with multiple myeloma, this 
regimen results in a 40% overall response rate, but few patients achieve a complete 
remission and the median duration of response is only 2 years.  The median survival is in 
the range of 3 years and few (<15%) survive 5 years.  More aggressive chemotherapy 
regimens, including VAD, VBMCP and M2, induce remissions more quickly but overall 
survival rates are not substantially improved (Alexanian and Dimopoulos, 1994). 
These poor outcomes led many investigators to explore high-dose chemotherapy regimens.  
In 1983, McElwain used melphalan 140 mg/m2 without stem cell support as a salvage 
therapy in nine patients with refractory myeloma and noted all patients responded to 
treatment with five patients achieving complete biochemical and bone marrow responses 
(McElwain and Powles, 1983).  This observation of dose-response led to a series of phase 
I/II trials with and without stem cell support in both newly diagnosed and refractory disease 
(Attal et al., 1992; Harousseau et al, 1995). 
A matched-pair analysis by the Arkansas group and SWOG comparing dose-intense with 
standard-dose therapy demonstrated the benefit of autologous HSC transplantation for the 
treatment of multiple myeloma (Barlogie et al., 1997).  Event-free (49 vs 27 months) and 
overall survivals (62+ vs 48 months) were improved for patients treated with dose-intense 
therapy as part of the initial treatment. 
A number of randomized studies comparing dose-intense therapy with autologous stem cell 
support to standard therapy regimens have been conducted.  The French Myeloma 
Intergroup reported a large-scale randomized trial (IFM 90) that randomized two hundred 


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patients to either conventional dose VMCP/VBAP or autologous bone marrow 
transplantation with melphalan and total body irradiation after four cycles of induction 
treatment (Attal et al., 1996).  The findings were strikingly in favor of the dose-intense 
approach with improvements in complete response rates (22% vs 5%) and median 
probabilities of event-free (27 months vs 18 months) and overall-survivals (60+ months vs 
37 months).  In contrast, the USIG found no difference in overall survival using the same 
transplant conditioning regimen but a much more intensive “standard” non-transplant 
chemotherapy regimen (Barlogie et al., 2006).  These authors also acknowledged that the 
combination of melphalan and TBI is now recognized as an inferior transplant regimen.   
The French group Myelome Autogreffe (MAG) achieved results comparable to the IFM 90 
trial; however, there was no significant difference in overall survivals as a result of 
unexpected prolonged survivals in the chemotherapy arm (Fermand et al., 2005). The 
Spanish PETHEMA group did not find a statistically significant difference in EFS and OS 
between chemotherapy and dose-intensive therapy (Blade et al., 2005). However, only 
patients who responded (CR: 15%; PR: 68%; MR: 17%) to conventional dose chemotherapy 
were randomized and patients in the chemotherapy arm were allowed to cross over into the 
dose-intensive therapy group. The Italian MMSG compared melphalan-prednisone to two 
courses of melphalan at 100 mg/m2 with autologous stem cell support (Palumbo et al., 
2004). They found significant improvement in CR and EFS in the transplant arm. The 
Medical Research Council Myeloma VII trial of 407 patients reported similar results for a 
comparison of six cycles of BCNU, doxorubicin, cyclophosphamide and melphalan to at 
least three cycles of doxorubicin, vincristine, methylprednisolone, and cyclophosphamide 
followed by melphalan at 200mg/m2 and autologous stem cell transplant (Child et al., 2003). 
This trial deserves special consideration in that it is the most recent of the randomized trials 
and was carried out in the era of more advanced supportive care and the availability of 
newer therapeutic agents.  It still showed a statistically significant advantage for HDT in 
terms of CR, EFS and OS.  In addition, it did not show any increase in treatment-related 
mortality relative to conventional therapy. These randomized trials, all of which showed a 
trend to, or significantly improved results for patients treated with dose-intense therapy, 
with the support of numerous phase II trials, clearly indicate that dose–intense therapy with 
autologous HSCT should be offered to appropriate patients as part of their initial treatment.  
The median EFS is remarkably constant (25-31 months).  It is more difficult to analyze OS 
results since OS partly depends on subsequent salvage therapy.  However, median OS was 
significantly longer in the three studies where differences in EFS were more marked.  In all 
studies, procedure-related death rate was <5% and not greater than that observed with 
conventional chemotherapy. 
 
 
 
 
 
 


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1.1.3 
Age as a Limiting Factor 
The plasma cell disorders strike older populations of patients; multiple myeloma is rare for 
patients under the age of 40 years.  The Arkansas group reported a slight increase in 60-
day mortality for patients over the age 65 undergoing transplantation for the treatment of 
myeloma (8% vs 2%).  However, median event-free (1.5 vs. 2.8 years) and overall survivals 
(3.3 vs. 4.8 years) were statistically similar (Siegel et al., 1999). 
 
Age has also not been found to be a significant predictor of transplant related mortality in 
other series.  An analysis of 383 consecutive transplants at Temple University actually 
noted poorer survival of younger patients compared to older patients, presumably a result 
of the willingness of physicians to offer aggressive treatment to younger patients with 
higher risk disease or co-morbid illnesses (Goldberg et al., 1998).  Conflicting data on this 
subject in at least 14 studies (6 no effect, 8 adverse) point to the need for patient selection 
criteria other than chronological age. 
 
MD Anderson Cancer Center (Qazilbash et al. 2007) treated 26 elderly myeloma patients 
(>70 years), who received a preparative regimen of melphalan 200 mg/m2 (19 patients), 
melphalan 180 mg/m2 (six patients) or melphalan 140 mg/m2 (one patient). Twenty-two 
of the 26 patients were alive after a median follow-up of 25 months (range=8-74). 
Responses (complete+partial response) were seen in 20 patients (77%), five (19%) of 
which were complete responses. Median PFS was 24 months, whereas median OS has not 
been reached. Cumulative incidence of 100-day TRM was 0%. Three-year PFS and OS 
were 39% (range=16-61) and 65% (range=35-83), respectively. Patients with relapsed 
disease at transplant and patients with an interval of >12 months between diagnosis and 
autotransplant, had a shorter OS (P=0.0004 and 0.04). 
1.2 Melphalan 
1.2.1. 
Melphalan Non-clinical Pharmacology  
Melphalan is a bifunctional alkylating agent that acts principally through covalent reactions 
with DNA, resulting in the formation of drug-DNA adducts with cross-linking of DNA 
strands (Samuels and Bitran, 1995).  Melphalan’s cytotoxic effects are related to its 
concentration and the duration of exposure to melphalan of the cell (Hall and Tilby, 1992).  
Table 1: Randomized Trials Comparing Conventional Chemotherapy vs. High-dose Therapy 
 
N 
Age 
MedianF/U 
CR rate (%) 
 
Median EFS (m) 
 
Median OS (m) 
CC 
HDT 
P 
 
CC 
HDT 
P 
 
CC 
HDT 
P 
IFM 90 
200 
<65 
7 yr 
5 
22 
<0.001 
 
18 
28 
0.01 
 
44 
57 
0.03 
MAG91 
190 
55-
65 
56 m 
NE 
NE 
 
 
19 
25 
0.05 
 
45 
42 
NS 
PETHEMA 
164 
≤65 
42 m 
11 
30 
0.002 
 
34 
42 
NS 
 
67 
65 
NS 
Italian MMSG 
195 
50-
70 
2 yr 
7 
26 
<0.001 
 
16 
28 
0.0036 
 
43 
58+ 
0.0008 
USIG 
50 
 
 
15 
17 
NS 
 
21 
25 
0.05 
 
53 
58 
NS 
MRC7 
407 
<65 
42 m 
8 
44 
<0.001 
 
19.6 
31.6 
<0.0001 
 
42 
54 
<0.001 
Abbreviations: CC=conventional chemotherapy, CR=complete remission, EFS=event free survival, HDT=high-dose 
therapy, OS=overall survival, NE=not evaluated, NS=difference not statistically significant. 


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Enhanced repair of DNA interstrand crosslinks may be a mechanism of resistance that 
develops after prior exposure to this drug (Spanswick et al., 2002).  Melphalan is actively 
transported into cells by the high-affinity L-amino acid transport system; glutamine and 
leucine compete for carrier uptake and high levels of these amino acids can reduce drug 
uptake.  Other drugs such as tamoxifen, chlorpromazine, and indomethacin can also impair 
melphalan uptake and accumulation. 
1.2.2. Clinical Pharmacokinetics and Pharmacodynamics 
Studies of the pharmacokinetics of oral melphalan were complicated by the highly variable 
absorption of the drug.  Moreover, studies of intravenous melphalan have also showed 
considerable inter-patient variability in plasma clearance.   Pinguet et al studied the 
pharmacokinetics of melphalan administered at a dose of 140 mg/m2 in combination with 
other chemotherapeutic agents to 20 patients undergoing autologous PBSC transplantation 
(Pinguet et al., 1997).  The median times to neutrophil and platelet recoveries were 16 and 
14.6 days, and the majority of patients (80%) developed WHO grade 3/4 stomatitis.  Plasma 
concentration profiles were biphasic and fitted with a two-compartment model.  The maximal 
concentration at the end of infusion averaged 7.94±3.73 mg/l (range, 1.65-14.5).  The mean 
elimination half-life and the mean residence time were 83.1±27.1 minutes (range, 51.6-
16681) and 98.7±26.9 minutes (range 59.5-166.9), respectively.  The volume of distribution 
averaged 1.00±0.62 l/kg (range 0.46-3.12) and total plasma clearance 548.3±300.0 
ml/min/m2 (range, 218.6-1378.8).   Plasma levels were below the limits of detection for all 
patients by 24 hours after melphalan administration.  These authors noted large inter-
individual variability of these pharmacokinetic parameters.  Total clearance of melphalan was 
significantly correlated with creatinine clearance (r=0.49, p<0.05).   A relationship between 
melphalan clearance and renal function was also described by Kergueris et al., but this 
relationship did not explain the large variation in inter-individual overall clearance of the 
drug (Kergueris et al., 1994).  Similar pharmacokinetic results were reported for 20 pediatric 
and 10 adult patients treated with melphalan 140 mg/m2 as a single agent (infused rapidly 
over 5 minutes; Gouyette et al., 1986).  For the adult patients, the elimination half-life (t½β) 
was 50±7 minutes for patients treated with 140 mg/m2 dose and 41±12 minutes for the higher 
dose of 180 mg/m2.  Plasma clearance averaged 525 ml/min/m2 at 140 mg/m2 and 532 
ml/min/m2 at 180 mg/m2.   
Melphalan undergoes hydrolysis in the circulation and the amount cleared by the kidneys is 
not well defined.  However, the toxicity of melphalan (hematological or gastrointestinal) is 
reported higher for patients with diminished renal function.  A study of nine patients given a 
melphalan dose of 5 mg/m2 (four of whom subsequently treated with 220 mg/m2) showed 
highly variable renal clearance of melphalan with the percentage of dose excreted unchanged 
in the urine ranging from 2.5% to 92.8% (Reece et al., 1988).    These authors speculated that 
the variation in renal clearance observed for these patients could account for the large 
variation in plasma clearance observed in all studies of melphalan pharmacokinetics. 
1.2.3. Clinical Toxicities of Melphalan 
Dose-related leukopenia, thrombocytopenia, anemia, usually with nadir 2-3 weeks and with 
recovery 4-5 weeks after dosing (without HSC support) will occur with moderate melphalan 
dose schedules.  Hematological toxicity is the most prominent serious toxicity associated with 


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the use of high-dose melphalan regimens, with neutrophil counts falling to <100/uL about 7 
days after administration.  However, initial hematological recovery occurs about 3 to 5 days 
later for patients given hematopoietic stem cell and cytokine support.  About 50% of patients 
will require blood component (red blood cells and/or platelet) support or will develop 
neutropenic fevers during the period of marrow hypoplasia. 
Dose-related nausea and vomiting beginning 2-4 hrs after dosing, peaking at 12 hrs, and 
persisting for several days, and delayed nausea and vomiting starting 24-48 hrs after 
administration and persist for multiple days to 3 or 4 weeks occurs with high doses of 
melphalan.  Stomatitis will occur in most patients can be almost completely prevented by 
prophylactic cooling of the mouth with ice during the infusion of melphalan.  A small 
proportion of patients will develop diarrhea. 
Melphalan is associated with a number of rare complications including:  hemolytic anemia, 
abnormal liver function tests with jaundice, renal insufficiency, atrial fibrillation, pulmonary 
fibrosis and interstitial pneumonitis, skin hypersensitivity, seizures (described in patients with 
renal failure receiving melphalan, hyponatremia and SIADH, secondary leukemia and 
myelodysplastic syndromes, anaphylaxis (rare), and potentially irreversible sterility. 
 
1.3 VELCADE (bortezomib) for Injection 
1.3.1.  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.  Bortezomib is currently approved by the United States Food and Drug 
Administration (US FDA) and it is registered in Europe for the treatment of multiple myeloma 
patients who have received at least one prior therapy. 
By inhibiting a single molecular target, the proteasome, bortezomib affects multiple signaling 
pathways.  The anti-neoplastic effect of bortezomib likely involves several distinct 
mechanisms, including inhibition of cell growth and survival pathways, induction of 
apoptosis, and inhibition of expression of genes that control cellular adhesion, migration and 
angiogenesis.  Thus, the mechanisms by which bortezomib elicits its antitumor activity may 
vary among tumor types, and the extent to which each affected pathway is critical to the 
inhibition of tumor growth could also differ.  Bortezomib has a novel pattern of cytotoxicity 
in National Cancer Institute (NCI) in vitro and in vivo assays (Adams et al., 1999).  In 
addition, bortezomib has cytotoxic activity in a variety of xenograft tumor models, both as a 
single agent and in combination with chemotherapy and radiation (Steiner et al., 2001; Teicher 
et al., 1999; Cusack et al., 2001; LeBlanc et al., 2002; Pink et al., 2002).  Notably, bortezomib 
induces apoptosis in cells that over express bcl-2, a genetic trait that confers unregulated 
growth and resistance to conventional chemotherapeutics (McConkey et al., 1999). 
Bortezomib is thought to be efficacious in multiple myeloma via its inhibition of nuclear factor 
B (NF-B) activation, its attenuation of interleukin-6 (IL-6)-mediated cell growth, a direct 
apoptotic effect, and possibly anti-angiogenic and other effects (Hideshima et al., 2001). 
 


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1.3.2. Non-clinical Pharmacology 
Pharmacokinetic (PK) and pharmacodynamic studies were conducted in the rat and 
cynomolgus monkey.  Upon intravenous (IV) bolus administration, bortezomib displays a 
rapid distribution phase (t½ <10 minutes) followed by a longer elimination phase (t½ 5–
15 hours).  Bortezomib has a large volume of distribution (range 5–50 L/kg).  The plasma PK 
profile is well described by a 2-compartment model. 
The pharmacodynamic action of bortezomib is well established and can be measured through 
an ex vivo assay (20S proteasome activity) (Lightcap et al., 2000).  This assay was used to 
determine the duration of drug effect in lieu of the PK data in the early preclinical toxicology 
studies as well as to set a guide for dose escalation in humans.  Following dosing with 
bortezomib in the rat and cynomolgus monkey, proteasome inhibition in peripheral blood had 
a half-life less than 24 hours, with proteasome activity returning to pretreatment baseline 
within 24 hours in monkey and within 48 to 72 hours in rat after a single dose of bortezomib.  
Further, intermittent but high inhibition (>70%) of proteasome activity was better tolerated 
than sustained inhibition.  Thus, a twice-weekly clinical dosing regimen was chosen in order 
to allow return of proteasome activity towards baseline between dose administrations. 
1.3.3. Non-clinical Toxicity 
Single-dose IV toxicity studies were conducted with bortezomib in the mouse, rat, dog, and 
monkey to establish the single-dose maximum tolerated dose (MTD).  The MTDs were 0.25 
mg/kg (1.5 mg/m2) and 0.067 mg/kg (0.8 mg/m2) in the 2 most sensitive species, rat and 
monkey, respectively. 
Repeat-dose multi-cycle toxicity studies of 3 and 6 months in the rat and 9 months in the 
monkey, each with 8-week recovery periods, were conducted to characterize the chronic 
toxicity of bortezomib when administered by the clinical route and regimen of administration.  
The MTD in the 6-month rat study was 0.10 mg/kg (0.6 mg/m2) and the key target organs 
were the gastrointestinal (GI) tract, hematopoietic and lymphoid systems.  The MTD in the 9-
month monkey study was 0.05 mg/kg (0.6 mg/m2) and the key target organs were the GI tract, 
hematopoietic and lymphoid systems, peripheral nervous system, and kidney.  Full or partial 
reversibility was observed for each of the toxicities described to date. 
In general, the nature of the toxicity of bortezomib is similar across species, and target organs 
of toxicity in animals have been largely predictive of human toxicity.  The toxicity of 
bortezomib in animals is characterized by a steep dose-response with mortality seen at dosages 
above the MTD.  The cause of death at acutely lethal dosages is considered to be related to 
indirect cardiovascular (CV) effects of hypotension and vascular changes with secondary 
bradycardia and the cause of death in long-term studies has been attributed to GI or 
hematologic toxicity.  The pharmacologic effects of bortezomib on the CV system have been 
extensively characterized and have demonstrated that indirect effects on CV function occur 
only at acutely lethal dosages and are abrogated by routine supportive care. 
Additional detailed information regarding the nonclinical pharmacology and toxicology of 
bortezomib may be found in the 2006 Investigator’s Brochure. 
 


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1.3.4. Clinical Pharmacokinetics and Pharmacodynamics 
The clinical pharmacology characterization of bortezomib has been determined from phase 1 
studies in subjects with solid tumors and hematological malignancies, and confirmed in 
phase 2 studies in subjects with multiple myeloma. 
Bortezomib demonstrates multi-compartmental pharmacokinetics. Following intravenous 
administration of 1.0 mg/m2 and 1.3 mg/m2 dose, the mean first-dose maximum observed 
plasma concentrations of bortezomib were 57 and 112 ng/mL, respectively in 11 patients with 
multiple myeloma and creatinine clearance values >50 mL/min participating in a 
pharmacokinetics study.  In subsequent doses, mean maximum observed plasma 
concentrations ranged from 67 to 106 ng/mL for the 1.0 mg/m2 dose and 89 to 120 ng/mL for 
the 1.3 mg/m2 dose.  The mean elimination half-life of bortezomib upon multiple dosing 
ranged from 40 to 193 hours.  Bortezomib is eliminated more rapidly following the first dose.  
Mean Total Body Clearances were 102 and 112 L/h following the first dose for doses of 1.0 
mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses 
for doses of 1.0 and 1.3 mg/m2, respectively.  Clinical experience has shown that the change 
in clearance does not result in overt toxicity from accumulation in this multidose regimen in 
humans. 
In subjects with advanced malignancies, the maximum pharmacodynamic effect (inhibition 
of 20S activity) occurred within 1-hour post dose.  At the therapeutic dose of 1.3 mg/m2 in 
subjects with multiple myeloma, the mean proteasome inhibition at 1-hour post dose was 
approximately 61%. 
The time course of proteasome inhibition in subjects is characterized by maximum inhibition 
observed within the first hour after administration, followed by partial recovery of proteasome 
activity over the next 6 to 24 hours to within 50% of the pretreatment activity.  On the Day 1, 
4, 8, and 11 schedule, variable (10%–30%) levels of proteasome inhibition have been 
observed at next scheduled dosing.  In theory, this advantage allows cells to recover 
proteasome activity for normal cellular housekeeping functions between doses. 
The relationship between bortezomib plasma concentrations and proteasome inhibition can be 
described by a maximum effect (Emax) model.  The Emax curve is initially very steep, with 
small changes in plasma bortezomib concentration over the range of 0.5 to 2.0 ng/mL relating 
to large increases in the percent inhibition (0–60%).  After that, a plateau occurs where 
marginal increases of proteasome inhibition are observed in spite of large changes in plasma 
bortezomib concentrations. 
1.3.5. Clinical Experience 
It is estimated that more than 55,000 patients have been treated with bortezomib, including 
patients treated through Millennium-sponsored clinical trials, Investigator-Initiated Studies, 
the US NCI Cancer Therapy Evaluation Program (CTEP), and with commercially available 
drug.  Bortezomib has been commercially available since 13 May 2003. 
The overall goal of the Millennium phase 1 program was to determine the MTD and dose-
limiting toxicity (DLT) of bortezomib in a number of therapeutic settings involving subjects 
with various advanced malignancies.  In a Phase I trial in patients with refractory hematologic 
malignancies, the MTD for a twice weekly for 4 weeks of a 42 day cycle was 1.04 mg/m2/dose, 


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with DLTs of thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise (Orlowski 
et al., 2002).  The toxicity was greatest during the third and fourth weeks of therapy. In the 3-
week schedule of bortezomib monotherapy (4 doses, given on Days 1, 4, 8, and 11 of a 21-
day treatment cycle), the DLT occurred at 1.56 mg/m2/dose (3 subjects with Grade 3 diarrhea 
and 1 with peripheral sensory neuropathy).  Therefore, the MTD at this schedule was 1.3 
mg/m2/dose.  In a 35-day treatment cycle with 4 weekly doses of bortezomib monotherapy, 
the MTD was 1.6 mg/m2/dose and DLT included hypotension, tachycardia, diarrhea, and 
syncope. 
In phase 1 clinical studies, anti-tumor activity was reported in subjects with NHL, multiple 
myeloma, Waldenström’s Macroglobulinemia, squamous cell carcinoma of the 
nasopharynx, bronchoalveolar carcinoma of the lung, renal cell carcinoma, and prostate 
cancer. 
The safety and efficacy of bortezomib in subjects with multiple myeloma were investigated 
in two phase 2 clinical studies, studies M34100-024 (subjects with first relapse) (Jagannath et 
al, 2004) and M34100-025 (subjects with second or greater relapse and refractory to their last 
prior therapy) (Richardson et al, 2003).  In M34100-025, 202 heavily pre-treated subjects with 
refractory multiple myeloma after at least 2 previous treatments received bortezomib, 1.3 
mg/m2 on Days 1, 4, 8, and 11 of a 21-day treatment cycle. The European Group for Blood 
and Marrow Transplant (EBMT) response criteria, as described by Blade (Blade et al., 1998) 
were utilized to determine disease response.  CRs were observed in 4% of subjects, with an 
additional 6% of patients meeting all criteria for CR but having a positive immunofixation 
test.  PR or better was observed in 27% of subjects, and the overall response rate (CR, PR and 
minor response [MR] combined) was 35%.  Seventy percent of subjects experienced stable 
disease or better. 
The phase 3 study (M34101-039) (Richardson et al, 2005), also referred to as the APEX study, 
was designed to determine whether bortezomib provided benefit (time to progression [TTP], 
response rate, and survival) to patients with relapsed or refractory MM relative to treatment 
with high-dose dexamethasone.  The study was also designed to determine the safety and 
tolerability of bortezomib relative to high-dose dexamethasone, and whether treatment with 
bortezomib was associated with superior clinical benefit and quality of life relative to high-
dose dexamethasone. A total of 669 patients were enrolled and 663 patients received study 
drug (bortezomib: 331; dexamethasone: 332).  Patients randomized to bortezomib received 
1.3 mg/m2 I.V. push twice weekly on days 1, 4, 8, and 11 of a 3-week cycle for up to eight 
treatment cycles as induction therapy, followed by 1.3 mg/m2 bortezomib weekly on days 1, 
8, 15, and 22 of a 5-week cycle for three cycles as maintenance therapy. Patients randomized 
to dexamethasone received oral dexamethasone 40 mg once daily on days 1 to 4, 9 to 12, and 
17 to 20 of a 5-week cycle for up to four treatment cycles as induction therapy, followed by 
dexamethasone 40 mg once daily on days 1 to 4 followed of a 4-week cycle for five cycles as 
maintenance therapy. The European Group for Blood and Marrow Transplant (EBMT) 
response criteria, as described by Blade (Blade et al., 1998) were utilized to determine disease 
response.  There was a 78% increase in TTP for the bortezomib arm. Median TTP was 6.2 
months for the bortezomib arm and 3.5 months for the dexamethasone arm (P<.0001). CR 
(complete response) + PR (partial response) was 38% with bortezomib vs. 18% with 
dexamethasone (P.0001). CR was 6% with bortezomib vs. 1% with dexamethasone 


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(P<.0001). The CR + nCR rate was13% with bortezomib vs. 2% with dexamethasone. In 
patients who had received only one prior line of treatment (bortezomib: 132; dexamethasone: 
119), CR + PR was 45% with bortezomib vs. 26% with dexamethasone (P=.0035). With a 
median 8.3 months of follow-up, overall survival was significantly longer (P=.0013) for 
patients on the bortezomib arm vs. patients on the dexamethasone arm. The probability of 
survival at one year was 80% for the bortezomib arm vs. 66% for the dexamethasone arm, 
which represented a 41% decreased relative risk of death in the first year with bortezomib 
(P=.0005). In patients who had received only one prior line of treatment, the probability of 
survival at one year was 89% for the bortezomib arm vs. 72% for the dexamethasone arm, 
which represented a 61% decreased relative risk of death in the first year with bortezomib 
(P=.0098). (Richardson et al., 2005). Updated response rates and survival data were reported 
for M34101-039 (Richardson ASH, 2005). The updated CR (complete response) + PR (partial 
response) rate was 43% with bortezomib. The CR + nCR rate was 16% with bortezomib. With 
a median 22 months of follow-up, overall survival was significantly longer for patients on the 
bortezomib arm vs. patients on the dexamethasone arm. The median overall survival was 29.8 
months (95% CI: 23.2, not estimable) for the VELCADE arm vs. 23.7 months (95% CI: 18.7, 
29.1) for the dexamethasone arm (hazard ratio = 0.77, P= 0.0272). The probability of survival 
at one year was 80% for the bortezomib arm vs. 67% for the dexamethasone arm (P=0.0002). 
Studies using bortezomib as monotherapy and in combination with other chemotherapy 
agents are continuing.  Potential Risks of bortezomib (this section reflects updates to our 
standard risks language that have been updated since I gave the modified version of the 
protocol several months ago. 
1.4. Combination of Bortezomib and Other Agents 
A pre-clinical study reported by the Dana Farber Jerome Lipper Multiple Myeloma Center 
demonstrated synergy in cell line kill between bortezomib and other agents such as 
doxorubicin and melphalan (Mitsiades et al., 2003).  Synergy was found with co-incubation 
of bortezomib with doxorubicin, or with pre-exposure to either of the drugs.  Bortezomib 
exposure after prior doxorubicin exposure achieved the greatest cell kill.  Myeloma cell lines 
known to be resistant to doxorubicin or melphalan confirmed sensitization by bortezomib, as 
did studies involving freshly isolated myeloma cells from patients known to be resistant to 
bortezomib or doxorubicin.  A proposed mechanism for this enhancement of chemosensitivity 
is the down-regulation of several effectors involved in the cellular response to genotoxic 
stress, restoring sensitivity to DNA-damaging chemotherapeutic agents. 
Berenson et al recently published a phase I/II trial of bortezomib and low-dose melphalan 
combination therapy for the treatment of patients with relapsed or refractory multiple 
myeloma (Berenson et al., 2006).  Bortezomib was administered from 0.7 to 1.0 mg/m2 on 
days 1, 4, 8, and 11 of a 28-day cycle for up to eight cycles, and oral melphalan was 
administered in escalating doses form 0.025 to 0.25 mg/kg on days 1 to 4.  Thirty-five patients 
were enrolled and dose-limiting grade 4 neutropenia in two of six patients in the highest dose 
cohort led to the assignment of bortezomib 1.0 mg/m2 and melphalan 0.10 mg/kg as the 
maximum-tolerated dose.  Responses were observed in 23 of 34 evaluable patients.  
Myelosuppression was the most prominent toxicity; Grade 1/2 neurotoxicity developed in 8 
patients and worsened in 4 of 15 patients with pre-existing neurotoxicity.  Diarrhea and 


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nausea/vomiting were observed at all dose levels and no relationship to drug dosage was 
evident. 
Hollmig et al described treatment of 37 patients with bortezomib and high-dose melphalan 
(Hollmig et al., 2004).  Bortezomib was dosed at 1.0 mg/m2 or 1.3 mg/m2 on days -4 and -1 
before autologous HSC transplantation, with melphalan (50-200 mg/m2) given on the same 
days for 26 patients and on day -1 only for 11 patients.  All patients achieved granulocyte 
(median, 13 days) and platelet (median, 17 days) recoveries.   Serious (grade 3/4) mucositis 
and/or diarrhea occurred in 14% and 29% of patients, respectively.  No transplant-related 
deaths were reported.  A partial or better response was observed in 73% of evaluable patients.  
This same group also reported the use of 3 or 4 fractions of high-dose melphalan given along 
with bortezomib (1.0 or 1.3 mg/m2) in a standard day 1, 4, 7, ±10 fashion (Pineda-Roman et 
al., 2006).  Maximum doses of melphalan reached 240-250 mg/m2.  Only 1 of 22 patients 
treated experienced significant (grade 2) mucositis with grade 3/4 diarrhea (primarily 
infectious) in 8 patients.  These reports suggest a safe starting dose of bortezomib in 
combination with high-dose melphalan of 1.0 mg/m2. 
A similar phase I trial of bortezomib and pegulated liposomal doxorubicin (PegLD) enrolled 
42 patients (24 with multiple myeloma) with advanced hematological malignancies (Orlowski 
et al., 2005).  Bortezomib dosing started at 0.9 mg/m2 and was advanced in a modified 
Fibonacci escalation with subsequent steps of 1.05, 1.2, 1.3, 1.4, and 1.5 mg/m2, and was 
given on days 1, 4, 8, and 11 of each 21-day cycle.  PegLD, 30 mg/m2, was given on day 4 of 
each cycle. A bortezomib dose of 1.3 mg/m2 was recommended for further study because of 
frequent dose reductions and delays at the MTD of 1.5 mg/m2.  Hematological toxicities were 
the most common, with fatigue being the most-common non-hematological toxicity.  Again, 
diarrhea was observed at all dose levels.  Of the 22 evaluable patients treated for myeloma, 8 
achieved a CR or very good PR, and another 8 achieved a PR. 
The combination of bortezomib and carboplatin was studied in a phase I trial involving 15 
patients with recurrent ovarian or primary peritoneal cancer (Aghajanian et al., 2005).  
Carboplatin was administered on day 1 at a dose of 5 (AUC), and bortezomib on days 1, 4, 8, 
and 11 of each three week cycle at dose levels of 0.75, 1, 1.3, and 1.5 mg/m2.  No dose-limiting 
hematological toxicities were observed; dose-limiting non-hematological toxicities were 
diarrhea, skin rash, and sensory peripheral neuropathy (all grade 3) and the highest dose level 
of 1.5 mg/m2, and the MTD was determined to be 1.3 mg/m2.  An overall response rate of 
47% was demonstrated, and one patient with platinum-resistant disease achieved a CR. 
We are conducting a phase I/II clinical study of bortezomib with dose-intense melphalan with 
autologous peripheral blood stem cell transplantation in patients with disease progression or 
less than partial response after a prior PBSCT (Rowley, et al,  2009).  Primary exclusion 
criteria are active infection at time of PBSCT, cardiac amyloid deposition, and creatinine 
clearance of <20 ml/min. Peripheral neuropathy of less than grade 4 is not an exclusion.  
Bortezomib is given on days -4 and -1 with melphalan 200 mg/m2 (actual weight) given on 
day -2 before PBSCT.  For the phase I study, bortezomib was given at rising doses of 1.0, 1.3, 
and 1.6 mg/m2.  Three patients were to be enrolled at each dose level, with an additional 3 
patients enrolled in case of a serious toxicity event at any level. An additional 20 patients are 
being enrolled in the phase II portion of the study with 15 patients enrolled as of 12/1/09 
(patient accrual will be completed before enrollment into this study).  


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Twelve patients (median age, 58 yrs) were treated in the phase I study with 6 patients treated 
at the 1.0 mg/m2 level after 1 patient experienced a serious adverse event (SAE) of prolonged 
diarrhea, and 3 patients treated at each of the subsequent levels. Eleven patients had 1 prior 
and 1 patient tandem prior cycles of dose-intense melphalan. All patients experienced the 
expected pancytopenia requiring red cell and/or platelet support.  Ten patients had febrile 
neutropenia with bacteremia identified in 3 patients. One patient had mild tumor lysis not 
requiring medical intervention.  Mucositis was minimal and comparable to PBSCT with 
melphalan alone. All patients engrafted at a median time to ANC>500/uL of 11 days (range, 
9-19) and platelet>20,000/uL of 14 days (range, 11-27). No other SAEs occurred in the phase 
I study beyond the usual events of high-dose therapy. No neurological SAEs, including severe 
peripheral neuropathies, were observed. A bortezomib dose of 1.6 mg/m2 was chosen for the 
phase II study.  
Fifteen patients (median age, 56 yrs) are now treated in the phase II study. Six patients had 
disease progression and 9 patients had less than a partial response (PR) after a prior PBSCT. 
All patients experienced pancytopenia and evaluable patients engrafted with median time to 
ANC>500/uL of 10 days (range, 8-13) and platelet>20,000 of 11 days (range, 9-65).  Eleven 
patients had febrile neutropenia with 3 patients with positive blood cultures and 1 patient with 
RSV bronchitis.  Three SAEs are reported in the phase II portion: 1 patient expired of 
complications of Candida krusei infection and 1 of MRSA sepsis (before ANC recovery). A 
third patient developed tumor lysis requiring dialysis. One patient had a dysphoric reaction to 
anti-emetics and did not receive the 2nd bortezomib dose.  No neurological SAEs attributable 
to this regimen were observed in this population.  
Patients underwent restaging studies at monthly intervals after transplantation with marrow 
examination at 3 and 12 months.  Response classification is in accordance to standard 
definitions. Three patients underwent subsequent allogeneic PBSC and 2 patients died of 
transplant-related complications and are not evaluable for response. Two patients succumbed 
to progressive disease. The remaining 20 patients are in ongoing follow-up. Eight patients 
including 6 of 11 patents with stable disease or minimal response after prior dose-intense 
melphalan achieved a CR. Six patients remain in continuous CR at 11+ to 23+ months 
(median, 15+ months) after PBSCT with 2 patients having disease progression at 12 and 26 
months after PBSCT.  
These data indicate that bortezomib can be added to dose-intense melphalan in this schedule 
with acceptable toxicities. Strikingly, 8 of 22 pts achieved CR after minimal response to dose-
intense melphalan alone or disease progression after a prior PBSCT, and 2 patients showed 
tumor lysis, indicating a synergistic effect of adding bortezomib to dose-intense melphalan. 
 


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2. 
Study Objectives 
 
2.1 Primary Objective: 
To compare the progression-free survivals of elderly patients with multiple myeloma treated 
with either high-dose melphalan or high-dose melphalan in combination with bortezomib 
 
2.2 Secondary Objective: 
To compare the response rate, overall survival, and regimen-related toxicities of elderly patients 
with multiple myeloma treated with either high-dose melphalan or high-dose melphalan in 
combination with bortezomib 


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3. 
Investigational Plan 
 
3.1  Overall Design and Plan of Study 
 
 
This is a single-institution, non-blinded phase III randomized study 
 
3.2 Patient Selection 
 
3.3 Inclusion Criteria 
3.3.1 
Confirmed diagnosis of multiple myeloma less than 12 months since 
initiation of systemic therapy 
 
 
3.3.2        ≥2x106 CD34+cells/kg available in cryopreservation 
 
 
3.3.3        Age >60 years at time of transplantation 
 
 
3.3.4           KPS 70-100% 
 
 
3.3.5           Recovery from complications of prior therapies 
 
 
3.3.6           Gender:  There is no gender restriction 
       3.4 Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the 
study. 
3.4.1 Diagnosis other than multiple myeloma 
3.4.2 Chemotherapy or radiotherapy within 8 days of initiating treatment in this 
study 
3.4.3 Prior dose-intense therapy within 56 days of initiating treatment in this 
study 
3.4.4 Uncontrolled bacterial, viral, fungal or parasitic infections  
3.4.5 Uncontrolled CNS metastases 
3.4.6 Known amyloid deposition in heart 
3.4.7 Organ dysfunction 
3.4.8 LVEF <40% or cardiac failure not responsive to therapy 
3.4.9 FVC, FEV1, or DLCO <40% of predicted and/or receiving supplementary 
continuous oxygen 
3.4.10 Evidence of hepatic synthetic dysfunction, or total bilirubin >2x or AST 
>3x ULN 
3.4.11 Calculated creatinine clearance <20 ml/min 
3.4.12 Sensory peripheral neuropathy grade 4 within 14 days of enrollment 
3.4.13 Karnofsky score <70% unless a result of bone disease directly caused by 
myeloma 
3.4.14 Life expectancy limited by another co-morbid illness 


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3.4.15 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 
3.4.16 Female subject is pregnant  or breast-feeding (women) or unwilling to use 
acceptable birth control methods (men or women) for twelve months after 
treatment. Confirmation that the subject is not pregnant must be 
established by a negative serum -human chorionic gonadotropin (-
hCG) pregnancy test result obtained during screening.  Pregnancy testing 
is not required for post-menopausal or surgically sterilized women. 
3.4.17 Documented hypersensitivity to melphalan or to bortezomib, boron or 
mannitol or any components of the formulation 
3.4.18 Patients unable or unwilling to provide consent 
3.4.19 Myocardial infarction within 6 months prior to enrollment or has New 
York Heart Association (NYHA) Class III or IV heart failure (see 
section 8.4), uncontrolled angina, severe uncontrolled ventricular 
arrhythmias, or electrocardiographic evidence of acute ischemia or active 
conduction system abnormalities. Prior to study entry, any ECG 
abnormality at screening has to be documented by the investigator as not 
medically relevant 
3.4.20 Patient has received other investigational drugs within 14 days before 
enrollment 
3.4.21 Serious medical or psychiatric illness likely to interfere with participation 
in this clinical study 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.5 Patient Evaluations 
3.5.1 Pre-transplant evaluation must be performed within 60 days of transplant, 
except for HLA, ABO and Rh typing 
3.5.2 History with full details of the patient’s prior treatments and responses 
3.5.3 Careful physical exam with determination of Karnofsky score and 
findings related to underlying malignancy 
3.5.4 Chemistry profile to include serum creatinine, , AST, alkaline 
phosphatase, and bilirubin 
3.5.5 CBC with differential 
3.5.6 ABO, Rh, red cell antibody screen, sickle cell screen (hemoglobin 
solubility) for African-Americans 
3.5.7 PT, PTT 
3.5.8 Serum pregnancy test, if female gender with child-bearing potential  
3.5.9 HIV, Hepatitis B, Hepatitis C and CMV serology 
3.5.10 Infectious disease testing, if previously documented positive, need not be 
repeated to comply with this requirement 
3.5.11 Creatinine clearance (measured) 
3.5.12 Disease Staging 
3.5.13 Serum and urine protein electrophoreses and immunofixation with 
measurement of monoclonal protein, serum free light chain 
3.5.14 Beta-2 microglobulin 
3.5.15 Radiological studies of any sites of bone pain if considered clinically 
significant 
3.5.16 Skeletal survey if not performed within 6 months of start of study 
treatment but may be deferred if PET CT completed within 6 months 
3.5.17 Pulmonary function tests with DLCO 
3.5.18 MUGA scan or Cardiac Echocardiogram 
3.5.19 Patients with a suspected diagnosis of amyloidosis will undergo 
echocardiography for the detection of cardiac involvement 
3.5.20 EKG 
3.6 Analysis of PBSC and Marrow Components 
3.6.1 CD34+ cell count 
3.7 Post-Transplant Evaluation 
3.7.1 Physical exam, daily until hematological recovery and resolution of 
serious regimen-related complications 


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3.7.2 Daily assessment of toxicity from day-1 until resolution of all Grade 3/4 
treatment-related toxicities 
3.7.2.1 Presence assessed and scored in accordance with NCI toxicity 
guidelines 
3.7.3 CBC daily from day 0 until ANC ≥500/ul on two sequential days after 
nadir reached (engraftment).  Thereafter, CBC recommended weekly 
until documentation of transfusion independence (platelet count 
≥20,000/ul without transfusion for ≥7 days) 
3.7.4 Chemistry profile including magnesium t.i.w. until documentation of 
engraftment, and then recommended weekly until stabilization of 
electrolytes is documented 
3.7.5 Record of all medications administered during inpatient course 
3.8 Post-transplant re-staging of disease 
3.8.1 Restaging by serum and urine should be done at 4 weeks intervals (±7 
days) starting at day +28 after transplantation for 3 months and then at 3 
months intervals until 3 years after transplantation or demonstration of 
disease progression requiring therapy, if earlier. 
3.8.2 24 hour urine for creatinine clearance, total protein, protein 
electrophoresis with quantitation of monoclonal protein by 
immunofixation, serum free light chain measurements at 4 week intervals 
(±7 days) starting at day +56 after transplantation for 3 months and then 
at 3 month intervals (or more frequently as clinically necessary) until 
demonstration of disease progression 
3.9 Study Treatments 
3.9.1 Study Medications 
3.9.1.1 Bortezomib (VELCADE) for Injection is a sterile lyophilized 
powder for reconstitution and is supplied in vials containing 
bortezomib and mannitol at a 1:10 ratio.  For example, vials 
containing 3.5 mg of bortezomib contain 35 mg of mannitol. Vials 
containing lyophilized bortezomib for Injection should be stored 
according to the label requirements.  For the United States, store at 
USP Controlled Room Temperature which is 25ºC (77ºF); 
excursions permitted from 15 to 30ºC (59 to 86ºF).  For Europe, do 
not store above 30ºC (86ºF).  To date, stability data indicate that the 
lyophilized drug product is stable for at least 18 months when 
stored under the recommended conditions. Stability studies are 
ongoing, and Millennium Pharmaceuticals, Inc. will notify the 
investigator should this information be revised during the conduct 
of the study. bortezomib is cytotoxic.  As with all cytotoxic drugs, 
caution is required when preparing and handling bortezomib 
solutions.  Cytotoxic drugs should only be handled by staff 


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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. The drug is available 
in sterile, single use vials containing 3.5 mg of bortezomib.  Each 
vial of bortezomib for Injection should be reconstituted under a 
laminar flow biological cabinet (hood) within eight hours before 
dosing with 3.5 mL of normal (0.9%) saline, Sodium Chloride 
Injection USP, so that the reconstituted solution contains 
bortezomib at a concentration of 1 mg/mL.  Prior to reconstitution 
the vials should remain in the cartons to protect them from 
light.  Dissolution is completed in approximately 10 seconds.  The 
reconstituted solution is clear and colorless, with a final pH of 5 to 
6.  Reconstituted bortezomib should be administered promptly and 
in no case more than 8 hours after reconstitution.  All materials that 
have been used for preparation should be disposed of according to 
standard practices.  A log must be kept of all disposed materials. 
3.9.1.2 Melphalan for Injection is a sterile lyophilized powder for 
reconstitution and will be obtained from the manufacturer in 
accordance with standard pharmacy purchasing criteria. Melphalan 
will be reconstituted by pharmacy staff, in accordance with usual 
pharmacy practices, immediately before patient infusion. 
Melphalan is a bifunctional alkylating agent that acts principally 
through covalent reactions with DNA, resulting in the formation of 
drug-DNA adducts with cross-linking of DNA strands.  
Melphalan’s cytotoxic effects are related to its concentration and 
the duration of exposure to melphalan of the cell.  Enhanced repair 
of DNA interstrand crosslinks may be a mechanism of resistance 
that develops after prior exposure to this drug. Melphalan is 
actively transported into cells by the high-affinity L-amino acid 
transport system; glutamine and leucine compete for carrier uptake 
and high levels of these amino acids can reduce drug uptake.  Other 
drugs such as tamoxifen, chlorpromazine, and indomethacin can 
also impair melphalan uptake and accumulation.  Studies of the 
pharmacokinetics of oral melphalan were complicated by the 
highly variable absorption of the drug.  Moreover, studies of 
intravenous melphalan have also showed considerable inter-patient 
variability in plasma clearance.   Pinguet et al studied the 
pharmacokinetics of melphalan administered at a dose of 140 


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mg/m2 in combination with other chemotherapeutic agents to 20 
patients undergoing autologous PBSC transplantation. The 
medians time to neutrophil and platelet recoveries were 16 and 14.6 
days, and the majority of patients (80%) developed WHO grade 3/4 
stomatitis.  Plasma concentration profiles were biphasic and fitted 
with a two-compartment model.  The maximal concentration at the 
end of infusion averaged 7.94±3.73 mg/l (range, 1.65-14.5).  The 
mean elimination half-life and the mean residence time were 
83.1±27.1 minutes (range, 51.6-166.81) and 98.7±26.9 minutes 
(range 59.5-166.9), respectively.  The volume of distribution 
averaged 1.00±0.62 l/kg (range 0.46-3.12) and total plasma 
clearance 548.3±300.0 ml/min/m2 (range, 218.6-1378.8).   Plasma 
levels were below the limits of detection for all patients by 24 hours 
after melphalan administration.  These authors noted large inter-
individual variability of these pharmacokinetic parameters.  Total 
clearance of melphalan was significantly correlated with creatinine 
clearance (r=0.49, p<0.05).   A relationship between melphalan 
clearance and renal function was also described by Kergueris et al., 
but this relationship did not explain the large variation in inter-
individual overall clearance of the drug (Kergueris et al., 1994).  
Similar pharmacokinetic results were reported for 20 pediatric and 
10 adult patients treated with melphalan 140 mg/m2 as a single 
agent.  For the adult patients, the elimination half-life (t½β) was 
50±7 minutes for patients treated with 140 mg/m2 dose and 41±12 
minutes for the higher dose of 180 mg/m2.  Plasma clearance 
averaged 525 ml/min/m2 at 140 mg/m2 and 532 ml/min/m2 at 180 
mg/m2. 
 
 
 
 
 
 
 
 
 
 
 
 
3.10 
  Outline of Treatment Plan 


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Patients will be randomly assigned to treatment arm A or treatment arm B 
 
Figure 1: Outline of Treatment Schema  treatment arm A 
 
Melphalan 200 mg/m2 day -1 
 
Autologous HSCT 
 
Figure 2: Outline of Treatment Schema treatment arm B 
Bortezomib 1.6 mg/m2 d-4 
 
Melphalan 200mg/m2 d-2 
 
Bortezomib 1.6mg/m2 d-1 
 
Autologous HSCT  
 
3.11 
Conditioning Regimens 
3.11.1 Treatment arm A  
3.11.2 Melphalan 
3.11.2.1 Melphalan is administered by rapid intravenous infusion via a 
central vein over 60 minutes 
3.11.2.2 The final dilution of melphalan is physically and 
chemically stable for 60 minutes and therefore will be 
administered within that time period 
3.11.2.3 Melphalan will be given as a single dose  
3.11.2.4 Patients are encouraged to “chew” ice for 15 minutes 
before through 1 hour after administration of melphalan 
3.11.2.5 Dosing will be based on body surface area calculated using 
actual body weight 
3.11.2.6 Patients will be hospitalized starting at least 1 hr before 
melphalan administration and continuing until ANC > 
500/uL. Hydration will be used for uro-protection for 2 
hours pre- and post melphalan infusion 
3.11.3 Treatment arm B 
3.11.4 Bortezomib 


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3.11.4.1 
Bortezomib is administered subcutaneously in the abdomen 
or anterior thighs 
3.11.4.2 
Bortezomib will be administered any time on day -4 and -1, 20 
hrs after the start of the melphalan infusion on day -2 
3.11.4.3 
Dosing will be based on body surface area calculated using 
actual body weight  
3.11.4.4 
Dexamethasone is administered at a dose of 20 mg i.v. daily 
on days -4 and -1 (with bortezomib).  Dexamethasone is 
administered at a dose of 10 mg i.v. as a component of the 
anti-nausea regimen on day -2 before melphalan 
administration 
3.12 Stem Cell Infusion 
3.12.1 Day 0 is defined as the day of first stem cell infusion. 
3.12.2 Additional cells may be infused on subsequent days if the volume of the 
HSC components is deemed too large for a single infusion  
3.12.3 HSC will be infused 18 hours or later after bortezomib infusion 
3.12.4 Day 0 should be fixed on a Monday – Friday, when possible 
3.12.5 All patients will receive unmodified HSCT (other than cryopreservation). 
These components will not be irradiated 
3.12.6 Cells will be infused according to HUMC Standard Practice guidelines 
3.13 Post-transplant Cytokine Administration. 
3.13.1 Patients will routinely receive filgrastim, 5 ug/kg sc, on days 3, 5, 7, 9 
and 10+ after stem cell transplantation.  Filgrastim dose may be rounded 
to vial size (e.g., <60kg:  300 mcg, > 60 kg:  480 mcg, >100 kg:  600 
mcg) 
3.14 Post-transplant Supportive Care 
3.14.1 Hospitalization:  Patients will be cared for in the inpatient or outpatient 
transplant units.  Patients will be discharged from the transplant unit 
when hematological recovery occurs, the patient is clinically stable, and 
all grade 3/4 toxicities have resolved Mucositis:   
3.14.1.1 
Patients may receive any anti-emetic regimen determined 
to be clinically appropriate 
3.14.1.2 
Patients may receive any anti-diarrhea regimen determined 
to be clinically appropriate 
3.14.2 Central line: Patients will have central venous access or peripheral 
inserted central catheter (PICC) suitable for blood component support and 
maintained according to HUMC Standard Practice guidelines 


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3.14.3 Infection prophylaxis:  Patients will receive prophylaxis HSV, bacterial, 
and fungal infections according to HUMC Standard Practice guidelines 
3.14.4 Blood component support:  Patients will receive transfusions in 
accordance with HUMC Standard Practice guidelines 
3.14.5 Nutrition:  Patients may receive enteral or parenteral alimentation if 
caloric or protein intake falls below daily basal needs 
3.14.6 Post-transplant treatment: There are no restrictions for administration of 
involved field radiation, chemotherapy, maintenance therapy, or surgical 
interventions after transplantation  
3.14.7 Bisphosphonates: Infusions of bisphosphonate therapy after 
transplantation should be considered for all patients 
3.14.8 Post-transplant vaccinations:  Vaccinations will be administered after 
transplantation in accordance with HUMC Standard Practice guidelines 
3.15 Disease Response 
3.15.1 Patients should undergo restaging of disease at 2 months and 3 months 
post-transplant then every 3 months thereafter as defined in section 3.8. 
3.16 Dosing of Agents 
3.16.1 Melphalan dosing will be based on actual body weight. 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. 
3.16.2 Bortezomib dosing will be based on actual body weight.  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   
3.16.3 Patient weight will be determined by the nursing or nutrition staff within 
7 days of start of conditioning 
3.16.4 Administration of Melphalan 


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3.16.4.1 
Melphalan will be dosed based on actual body weight at a 
dose of 200 mg/m2 and infused on day -1 (Arm A) or day -2 
(Arm B) 
3.16.4.2 
Administer melphalan IV over 60 minutes through a central 
catheter.  Rapid infusion may result in dizziness, nasal 
stuffiness, rhinorrhea, or nasal congestion during or 
immediately after infusion 
3.16.4.3 
Administer early in the day 
3.16.4.4 
Have patient empty bladder frequently 
3.16.4.5 
Patients will receive hydration before and after administration 
of melphalan 
3.16.4.6 
“Chewing” on ice may decrease the severity of oral mucositis 
and is encouraged for all patients starting 15 minutes before, 
during, and for 60 minutes after the infusion of melphalan  
3.16.4.7 
Patients will receive an anti-emetic regimen such as lorazepam 
1 mg i.v., dexamethasone 10 mg i.v., and Ondansetron 12mg 
i.v. 30 minutes before melphalan infusion 
3.16.5 Administration of Bortezomib 
3.16.5.1 
Bortezomib will be dosed based on actual body weight 
administered subcutaneously on day -4, and day -1 before 
HSC infusion 
3.16.5.2 
Bortezomib is supplied as a lyophilized white powder in 3.5 
mg single-dose vials 
3.16.5.3 
Bortezomib is reconstituted with 1.2 ml sterile water for 
injection, without shaking 
3.16.5.4 
Administration 
3.16.5.4.1 Subcutaneously in anterior thighs or abdomen..  Each 
vial is for a single use administration.   
3.16.5.4.2 Second dose of bortezomib will be no less than 20 hrs 
after melphalan administration 
3.16.5.4.3 Dexamethasone, 20 mg i.v., will be given as a pre-
medication, before each dose of bortezomib 
3.17 Pre-Transplant Therapy 
Chemotherapy and/or radiation therapy may be given to reduce tumor bulk as 
determined on clinical grounds.  The referring oncologist may be asked to administer 
this therapy.  The prior therapies are not specified by this protocol 


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3.17.1 Patients will not proceed to dose-intense therapy any sooner than 8 days 
after completion of the most recent cycle of chemotherapy or 
radiotherapy  
3.17.1.1 
The timing of therapy is in reference to the dose of melphalan 
3.17.1.2 
Therapy with should be discontinued no less than 7 days 
before initiation of bortezomib 
3.17.2 Collection of Autologous Hematopoietic Stem Cells 
The methods of collection of hematopoietic stem cells are not specified by this 
protocol 
 
3.18 Treatment Assignment 
Patients will be assigned to treatment in a randomized fashion with stratification 
for factors associated with risk of relapse for FISH factors associated with 
aggressive disease (e.g.: t(4:11), del13q, elevated B2M at diagnosis). 
3.19 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.   
Melphalan will be supplied in vials as open-label stock.  Both the box label and vial label 
will fulfill all requirements specified by governing regulations.  
3.20 Concomitant Treatment 
3.20.1 Required Concurrent Therapy 
 
 
Not applicable.  Patients will receive standard care 
 
        3.20.2 Prohibited Concurrent Therapy 
Any investigational agent  
3.21 Treatment Compliance 
All drug will be administered to eligible patients under the supervision of the 
investigator or identified sub-investigator(s).  The pharmacist will maintain records of 
drug receipt (if applicable), drug preparation, and dispensing, including the applicable 
lot numbers, patients’ height, body weight, and body surface area, and total drug 
administered in milliliters and milligrams.  Any discrepancy between the calculated dose 
and dose administered and the reason for the discrepancy must be recorded in the source 
documents. 
3.22 Duration of Treatment and Patient Participation 
Patients will be hospitalized until  resolution of serious adverse events.  Patients will 
then be followed, indefinitely, for survival and duration of response to the treatment 
received. 


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3.23 Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time 
for any reason, without prejudice to their medical care.   
x  The primary reason for a patient’s withdrawal from the study is to be recorded in the source 
documents. The patient will be followed for study endpoints, per study guidelines, unless the 
patient withdraws consent for study participation.  


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4. 
Adverse Events 
4.1 Definitions 
4.1.1 Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product, which does not necessarily have a causal relationship with the 
treatment.  An adverse event can be any unfavorable and unintended sign (eg, including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
drug, whether or not it is considered to be drug related.  This includes any newly occurring 
event or previous condition that has increased in severity or frequency since the administration 
of drug. 
4.1.2 Serious Adverse Event Definition 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that: 
 Results in death. 
 Is life-threatening.  Life-threatening means that the patient was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
 Requires inpatient hospitalization or prolongation of existing hospitalization.  
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered AEs if the illness or disease 
existed before the patient was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (eg, surgery performed earlier than planned). 
 Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a persons’ ability to conduct normal life functions. 
 Is a congenital anomaly/birth defect. 
 Is an important medical event.  An important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in 
the definitions for SAEs.  Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.   
Clarification should be made between the terms “serious” and “severe” since they ARE NOT 
synonymous.  The term “severe” is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as a severe headache).  This is NOT the same as 
“serious,” which is based on patient/event outcome or action criteria described above and are usually 
associated with events that pose a threat to a patient’s life or functioning.  A severe adverse event 
does not necessarily need to be considered serious.  For example, persistent nausea of several hours 


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duration may be considered severe nausea but not an SAE.  On the other hand, a stroke resulting in 
only a minor degree of disability may be considered mild, but would be defined as an SAE based 
on the above noted criteria.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
4.2 Procedures for AE and SAE Reporting 
Investigator-sponsor must report all serious adverse event (SAE) regardless of relationship with any 
study drug or expectedness to the IRB as required by the institution.  
 
Intensity for each adverse event, including any lab abnormality, will be determined by using the 
NCI CTCAE, version 3.0, as a guideline, wherever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
 
4.3 Assessment of Toxicity 
 
4.3.1. Common Terminology Criteria for Adverse Events (CTCAE) will be used for the 
assessment and grading of all toxicities experienced by patients enrolled into this 
study (htt;:///ctep.cancer.gov/forms/CTCAE_Index.pdf). 
a. If the nature of the adverse experience is listed in the CTCAE, the maximum 
grade and time of maximum grade will be reported. 
b. If the adverse experience is not listed on the NCI CTG Expanded Toxicity 
Criteria Appendix D, report the toxicity grade using the following criteria: 
Grade 1=  Mild: an adverse experience which is easily tolerated by the 
patient, causing minimal discomfort and not interfering with 
everyday activities. 
Grade 2 = Moderate: an adverse experience which is sufficienty 
discomforting to interfere with normal every day activities. 
Grade 3 = Severe: an adverse experience which is incapacitating and 
prevents normal every day activities. 
Grade 4 = Life Threatening: an adverse experience which places the patient 
at immediate risk of death. 
 
4.3.2. Assessment of Causality 
 
 
a. Every effort should be made by the investigator to explain each adverse 
experience and assess its relationship, if any, to study drug treatment.  
Causality should be assessed using the following categories: Not Related, 
Unlikely, Suspected (Reasonable Possibility), Probable. 
Not related:  The adverse experience is definitely not related to the test drug. 
Unlikely: There are other, more likely causes and the drug is not suspected as 
a cause. 
Suspected (reasonable possibility):  A direct cause and effect relationship 
between the drug and the adverse experience has not been demonstrated but 
there is a reasonable possibility that the experience was caused by the drug. 


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Probable: There probably is a direct cause and effect relationship between the 
adverse experience and the study drug. 
b. The degree of certainty with which an adverse experience is attributed to 
drug treatment (or alternative causes, e.g.: natural history of the underlying 
diseases, concomitant therapy, etc.) will be determined by how well the 
experience can be understood in terms of one or more of the following. 
Known pharmacology of the drug 
Reaction of similar nature being previously observed with this drug or class 
of drug.  The experience having often been reported in literature for similar 
drugs as drug related e.g.: skin rashes, blood dyscrasia.  The experience being 
related by time to drug ingestion terminating with drug withdrawal 
(dechallenge) or reproduced on rechallenge.   
4.3.3. Follow-up of Adverse Experiences 
a. 
Patients with adverse experiences grade 3/4 will be actively followed 
until the event has subsided (disappeared) or until the condition has 
stabilized. 
b. 
Adverse events, both serious and non-serious, and deaths that occur 
during the patient’s study participation will be recorded in the source 
documents.  All SAEs should be monitored until they are resolved or are 
clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).   
 
 
 
 
 
 
 


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5. Statistical Evaluation 
5.1.Primary Objective 
The primary objective of this randomized Phase III trial is to compare two different treatment 
regimens for multiple myeloma with respect to three-year progression-free survival (PFS). In 
particular, the study will provide us with an evaluation of whether the high-dose combination 
treatment increases the progression-free survival over the standard high-dose treatment. All 
the patients in the first arm receive a single high-dose of melphalan as the conditioning 
regimen for the autologous hematopoietic stem cell transplant (treatment arm A), the second 
arm receives melphalan and bortezomib a conditioning regimen for the autologous 
hematopoietic stem cell transplant (treatment arm B).   
Patients are considered a failure with respect to PFS if they die or experience disease 
progression or relapse.  The time to this event is the time from transplantation (day 0) to 
relapse/progression, initiation of non-protocol anti-myeloma therapy, or death from any cause.  
Subjects alive without confirmed disease progression will be censored at the time of last 
disease evaluation.  Deaths without progression are treated as failures no matter when they 
occur.   
 
5.2.Secondary Objective 
 
Secondary endpoints will include: 
a. Overall survival (OS):  Defined as time from the first dose of administration to death 
from any cause. 
b. Overall response rates: Defined as the composite endpoint of response to treatment 
which includes Complete Response (CR), Partial Response (PR), stable disease (SD) as 
defined in International Response Criteria. We will also analyze Complete Response 
rate.  
c. Univariate analyses of the risk of progression/relapse and mortality: In addition, 
multivariate analyses of the risk of progression/relapse and overall mortality will be 
conducted to assess influence of variables measured after the start of treatment. 
d. Regimen-related toxicity:  Graded and presented in a descriptive nature. 
 
Descriptive analysis of baseline characteristics and demographics in the two-treatment arms 
study will be performed in the following manner. Continuous measurements will be 
summarized as mean (SD) or median (inter-quartile range) based on whether or not the data 
come from a normal distribution as validated by Shapiro-Wilks test of normality. Categorical 
measurements will be summarized as frequency (percentage). Proportion of overall survival 
will be estimated by the Kaplan-Meier product limit method. The univariate probability of the 
relapse and treatment–related mortality (TRM) will be calculated using cumulative incidence 
function. 
 
5.3.Accrual, Registration and Follow-up 
 
The targeted sample size is 208 (allowing intensive analysis and drop-out) subjects.  It is 
estimated that four years of accrual will be necessary to enroll this number of subjects.   
HUMC treats about 150-170 of patients with this diagnosis every year, about half of who are 
believed eligible for this study. It is assumed that patients will enroll into the study uniformly 
over the accrual period. 


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The randomization will be stratified by risk status (high, low) where 156 high risk patients and 
52 low risk patients are enrolled assuming 3 (high):1 (low) ratio. High risk myeloma patients 
on this protocol are defined as having a serum Beta 2 microglobulin level > 4 mg/L; and/or 
abnormalities of chromosome 13 on standard metaphase karyotype analysis; and/or 
abnormalities of chromosome 17 or translocation 4:14 or 14:16 by FISH analysis at any time 
prior to transplant.  Standard risk myeloma patients on this protocol are defined as having a 
serum Beta 2 microglobulin level < 4 mg/L and absence of cytogenic findings described above.  
Patients with no karyotype analysis or failed analysis are assumed to not have chromosome 13 
abnormalities.   
 
After eligibility is established, subjects will be randomized in equal numbers to the melphalan- 
HSCT (104), and melphalan and bortezomib-HSCT (104) arms. It is assumed that patients 
will enroll into the study uniformly over the accrual period. 
 
All subjects will be “on-study” for three years post-transplant, during which they will be 
monitored for the effects of treatment through regular clinic.  With four years of planned 
accrual, and a minimum of three years of additional follow-up post-transplant, subjects will be 
followed for progression-free survival for at least 36 months. 
 
5.4.Sample Size and Power Calculations 
 
In this section, the power of the analysis of time to progression or death is considered and 
performed based on the proportion surviving without progression at three years.  The power of 
a two-sample one-sided log-rank test of surviving probability was calculated using PASS 14.   
 
The study design considers PFS at three-years post-transplant ranging from 36% to 56%.  The 
control, arm A, is assumed to have PFS of 36%. The new regimen consisting of melphalan and 
bortezomib in arm B could increase PFS to 56%.  Thus, using a desired power of 90%, for this 
one-side log-rank test sequentially evaluated at three timepoints (including interim analyses), at 
2.5% level of significance, two-year accrual, three-year follow up, we obtained the total sample 
of 208 with 104 subjects in the arm A and 104 subjects in arm B. This calculation achieved 
power >= 90.15%. Among 208 patients, 156 high risk patients and 52 low risk patients will be 
assumed to reflect 3:1 ratio at the beginning of trial. A randomization schedule was created for 
each risk status cohort and a set of two boxes of sealed envelopes containing the randomized 
treatment assignment has been maintained by designated members of the study team. 
 
The sequential analysis sample calculation was based on O’Brien-Flemming spending function. 
 
5.5.Efficacy analysis 
 
This is a phase III study comparing transplantation with high-dose melphalan to high-dose 
melphalan and bortezomib in patient 60 years or older with a diagnosis of multiple myeloma.   
 
5.6.Statistical Hypothesis 
 
The null hypothesis is that the 3 year progression-free survival rate in treatment arm A 
is 36%. The alternative hypothesis for this study posits that the treatment plan consisting 


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autologous transplantation with melphalan-bortezomib (treatment arm B) will increase 
the 3 year progression-free survival to 56% which is 20 % more than PFS in arm A.  
Thus, we will evaluate the hypotheses 
  
HO: SA(3) ≥SB(3)  
  
HA: SA(3) < SB(3)  
where SA(3) = the three year progression free surviving proportion of arm A which is assumed 
to be 0.36, SB(3) = the three year progression free surviving proportion of arm B. To account 
for heterogeneity of outcome due to risk status of patients in the treatment arms, the analysis of 
the comparison will be stratified on risk status. Thus, a one-sided log-rank test stratified on risk 
status (high risk 3:low risk1) will be conducted to determine if autologous transplantation with 
high-dose melphalan-bortezomib improves the progression-free survival that in over high-dose 
mephalan alone using a 2.5% level of significance.   
 
5.7.Primary endpoints 
 
To compare the PFS at 3 years between the two treatment arms each allocated 104 subjects. 
This sample size calculation is based on the assumption that the expected PFS of the standard 
transplant arm (melphalan 200 mg/m2) is 36% at 3 years (CIBMTR data). 
 
The primary analysis will include all randomized subjects, classified according to their 
randomized treatment assignment; irrespective of treatment actually received [intent-to-treat].  
The treatment arms will be compared using a one-sided log-rank test. All tests will be 
performed using the significance level of 2.5%.  
 
Analysis of PFS using a Cox proportional hazards mode will be conducted while adjusting for 
imbalance in other risk factors. To fit the multivariate model, a stepwise backward selection 
procedure will be used while considering the type of conditioning regimen (melphalan versus 
Melphalan with bortezomib), relapse risk status (low risk, high risk), age at transplant and  
Karnosfky performance score (<90 versus ≥90 ). An examination of the goodness-of-fit will 
be performed using Grambsch-Therneau and Martingale residual plots and lowess smooth of 
Cleveland. Covariates yielding a p-value of 0.05 or less will be an indication of statistical 
significance.  The proportionality assumption for Cox regression will be examined by 
introducing a time-dependent covariate for each risk factor and outcome. The stratified Cox 
proportional hazards model will be also performed to see the treatment effect in each of high 
and low risk group. This analysis will be presented in terms of relative risks (RR) along with 
the corresponding p values for each covariate. 
5.7.1.Planned Sequential Analyses for Efficacy and Futility 
Planned interim analyses for futility and efficacy will first be conducted one year after the 
completion of accrual, and will be repeated at 2 years post accrual completion.  If accrual is 
completed in three years, the interim analyses will be performed at 48 and 60 months after 
study launch.   
 
The rationale for conducting the first sequential analysis for futility and efficacy one year after 
the completion of accrual is a desire to avoid premature termination of accrual to a study arm 
based on short term trends that may later reverse.  The goal of the trial is to assess long-term 
PFS and overall survival.  The use of a sequential monitoring boundary will permit annual 
inspections of the data in the latter years of the trial while controlling the type I error of falsely 


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reporting a treatment difference.  
 
Analyses will be reported to the Data and Safety Monitoring Board (DSMB), whose 
members meet monthly.  The data will be presented by treatment arm, but the identity of the 
arms will be coded.   
 
Sequential analyses for efficacy will consist stratified log-rank tests comparing the two 
conditioning regimen.  All testing will be performed at 2.5% level of significance.  The p-
value is further adjusted for group sequential monitoring using O'Brien Fleming boundaries 
to conserve type I error.  
 
5.7.2. Operating Characteristics of Sequential Design 
 
Interim analyses planned at 1 and 2 years in addition to the final 3 years after the close of 
accrual, will operate using the O’Brien-Flemming spending function. The observed value 
of the one-sided log-rank will be compared to 3.200, 2.141 and 1.69478 boundaries.  If the 
value is less than the boundary at t each interim analysis prior to the final analysis, then trial 
shall continue to the phase. 
 
Details when Spending = O'Brien-Fleming, S1 = 0.3600, S2 = 0.5600 
 
 
Lower 
Upper 
Nominal 
Inc 
Total 
Inc 
Total 
Look 
Time 
Bndry 
Bndry 
Alpha 
Alpha 
Alpha 
Power 
Power 
1 
1.0000 
 
3.20010 
0.000687 
0.000687 
0.000687 
0.067817 
0.067817 
 
2 
2.0000 
 
2.14080 
0.016145 
0.015688 
0.016375 
0.541227 
0.609045 
 
3 
3.0000 
 
1.69478 
0.045059 
0.033625 
0.050000 
0.291699 
0.900744 
 
Drift 2.95809 
 
 
 
O'Brien-Fleming Boundaries with Alpha = 0.05
Upper
Lower
Z Value
Look
-2
-4
-6
-8
-10
0
2
4
0.5
1.0
1.5
2.0
2.5
3.0


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Otherwise, the trial will be terminated due to overwhelming significant increase in PFS 
above that in the standard treatment. 
 
5.8.Secondary endpoints 
 
Secondary endpoints will include: 
- Overall survival (OS):  Defined as time from the first dose of administration to death from 
any cause. 
- Overall response rates: Defined as the composite endpoint of response to treatment which 
includes Complete Response (CR), Partial Response (PR), stable disease (SD) as defined 
in International Response Criteria. We will also analyze Complete Response rate.  
- Univariate analyses of the risk of progression/relapse and mortality: In addition, 
multivariate analyses of the risk of progression/relapse and overall mortality will be 
conducted to assess influence of variables measured after the start of treatment. 
- Regimen-related toxicity:  Graded and presented in a descriptive nature. 
 
5.8.1. Response to Treatment 
 
The rates of complete remission (CR), and very good partial remission (VGPR) according to 
the International Uniform Response Criteria will be calculated at three years after 
randomization.  The analyses of the three-year response rates are planned as soon as those 
data become available in all subjects, at one and two years after the close of accrual.  The 
comparison of the response rate to the transplant with respect to the overall and CR 
component be performed using Mantel-Haenszel Test stratified on  risk status. 
 
5.8.2. Overall Survival 
 
The event is death from any cause. The time to this event is the time from randomization to 
death, loss to follow-up or the end of the study, whichever comes first.  Patients alive at the 
time of last observation are considered censored.  The Kaplan-Meier estimate of survival will 
be estimated separately for each treatment-group. For treatment comparisons, a log-rank test, 
conducted at a one-sided significance level of .025 analogous to the analysis of PFS described 
above. In addition, a stratified log-rank test will be performed to examine  the treatment effect 
in high or low risk group.  
 
A comparative analysis of risk outcomes relapse/progression, TRM, and overall mortality 
will be conducted while adjusting for imbalance in other risk factors using a stratified Cox 
proportional hazards model. To fit the multivariate model, a stepwise backward selection 
procedure will be used while considering the type of conditioning regimen (melphalan versus 
Melphalan with bortezomib), relapse risk status (low risk, high risk),  age at transplant and  
Karnosfky performance score (<90 versus ≥90 ).  An examination of the goodness-of-fit will 
be performed using Grambsch-Therneau and Martingale residual plots and lowess smooth of 
Cleveland. Covariates yielding a p-value of 0.05 or less will be an indication of statistical 
significance.  The proportionality assumption for Cox regression will be validated by 
introducing a time-dependent covariate for each risk factor and outcome.  This analysis will 
be presented in terms of relative risks (RR) along with the corresponding p values for each 
covariate. 
 


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5.8.3. Safety Analysis 
 
Safety Analysis will be performed on all patients who have at least one dose of medication 
on either treatment arms over the course of this study.  The severity of the toxicities will be 
graded according to the NCI CTCAE v3.0 whenever possible.  Events during the first 100 
days after transplantation will be considered possibly related to the transplant for this 
analysis.  Regimen-related toxicity will be graded and presented in a descriptive nature as 
incidence rates and corresponding 95% confidence intervals.  
 
5.8.3.1.Safety Monitoring Endpoints 
 
The incidence of toxicities of grade 3 or higher toxicities (CTCAE version 3.0); the 
incidence of probable viral, fungal, and bacterial infections; and the incidence of treatment-
related morality, i.e., from causes other than relapse or progression, will be recorded for 
each patient at set intervals over the course of the study.  Safety data will be described in a 
variety of ways, both graphical and tabular, and incidence will be compared across time 
points and treatment arms.  The Data and Safety Monitoring Board will be presented with a 
comprehensive semi-annual report that will contain both solicited and unsolicited adverse 
event reports. 
 
5.9.Stopping rules 
 
If the non-relapse mortality rate in the experimental group receiving bortezomib within the first 
3 month post exceeds 10% then the study will be stopped.  It is assumed that the non-relapse 
mortality in the standard high dose melphalan regimen is 3%.  Resumption of patient accrual 
will only be permitted after review of interim results by the Institutional Review Board and the 
Data Safety Monitoring Board.   
 
5.10. Monitoring Compliance. 
 
 Patients enrolled into the study will monitored for treatment actually received. Failure to 
comply with study conditioning regimen would first trigger an intervention to improve 
compliance. 
 
5.11. Data Management and Analysis 
 
Case report forms will be created for management of data collected during this study.  A 
database in Access will be created based on the case report forms. All study data will be 
imported into SAS and data management will be utilized to flag, and generate queries on out 
of range data issues until they are resolved. All analysis will be performed using SAS software 
version 9.2 (SAS Institute Inc. Cary, NC).    
 


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6. Administrative requirements 
6.1. Good Clinical Practice 
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
drug as described in the protocol and Investigator’s Brochure.  Essential clinical documents 
will be maintained to demonstrate the validity of the study and the integrity of the data 
collected.  Master files should be established at the beginning of the study, maintained for 
the duration of the study and retained according to the appropriate regulations. 
6.2. Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration 
of Helsinki.  The IRB/IEC will review all appropriate study documentation in order to 
safeguard the rights, safety and well-being of the patients.  The study will only be conducted 
at sites where IRB/IEC approval has been obtained.  The protocol, 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. 
6.3. Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from   
either the patient or his/her guardian or legal representative prior to study participation.  The 
method of obtaining and documenting the informed consent and the contents of the consent 
will comply with ICH-GCP and all applicable regulatory requirement(s). 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for treatment of the underlying disease.  All potential risks associated 
with the use of  bortezomib, melphalan and HSCT will be discussed as objectively as 
possible.  It will be explained that patients offered this treatment have advanced malignancy 
with life expectancy of months to no more than 1-2 years with conventional treatments.  
Informed consent from the patient will be obtained using the IRB-approved consent form 
describing this protocol.  The patient has the right to review and correct the results of the 
pre-transplant evaluation. 
6.4. Protocol  Registration 
All patients will be assigned a unique patient number (UPN) in accordance with HUMC 
Standard Practice. 
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 patient’s confidentiality will be maintained and will not be made 
publicly available to the extent  permitted by the applicable laws and regulations. 
 
 


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6.6. Record Retention 
The investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement)s).  The licensed medical records department, affiliated with the 
institution where the patient receives medical card, maintains all original inpatient and 
outpatient chart documents. 
6.7. Investigation New Drug Exemption 
All of the drugs employed in this protocol are commercially available and an IND 
exemption is not required for the conduct of this study.  The study will be conducted in 
accordance with current Good Clinical Practice guidelines. 
 
 


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7. Karnofsky Performance Status Scale 
The following table presents the Karnofsy performance status scale1: 
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 
 
1 
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. 
 


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8. Body Surface Area and Creatinine Clearance Calculations 
Body surface area (BSA) should be calculated using a standard nomogram that yields the 
following results in meters squared (m2): 
BSA = 
 
or 
BSA = 
3600
)
(
)
(
kg
Wt
cm
Ht

 
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as follows: 
 
CrCl (ml/min) =  (140-age) (actual wt in kg)        
                                         72 x serum creatinine (mg/dl) 
For females use 85% of calculated CrCl value. 
Note: In markedly obese patients, the Cockroft-Gault formula will tend to overestimate the 
creatinine clearance. (Adipose tissue tends to contribute little creatinine requiring renal 
clearance.) 12.0 New York Heart Association Classification of Cardiac Disease 
3131
)
(
)
(
lbs
Wt
inches
Ht



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9. NYHA 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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10. Declaration of Helsinki 
World Medical Association Declaration of Helsinki: 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, 
Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th 
WMA General Assembly, Somerset West, Republic of South Africa, October 1996 and the 52nd 
WMA General Assembly, Edinburgh, Scotland, October 2000 
INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as a statement of 
ethical principles to provide guidance to physicians and other participants in medical research 
involving human subjects.  Medical research involving human subjects includes research on 
identifiable human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people.  The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my patient will be my first consideration," and the International Code 
of Medical Ethics declares that, "A physician shall act only in the patient's interest when 
providing medical care which might have the effect of weakening the physical and mental 
condition of the patient." 
4. Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects. 
5. In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the aetiology 
and pathogenesis of disease.  Even the best proven prophylactic, diagnostic, and therapeutic 
methods must continuously be challenged through research for their effectiveness, efficiency, 
accessibility and quality. 
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human beings and 
protect their health and rights.  Some research populations are vulnerable and need special 
protection.  The particular needs of the economically and medically disadvantaged must be 
recognized.  Special attention is also required for those who cannot give or refuse consent for 
themselves, for those who may be subject to giving consent under duress, for those who will 
not benefit personally from the research and for those for whom the research is combined with 
care. 
9. Research Investigators should be aware of the ethical, legal and regulatory requirements for 
research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration. 


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BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
1. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
2. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources 
of information, and on adequate laboratory and, where appropriate, animal experimentation. 
3. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
4. The design and performance of each experimental procedure involving human subjects should 
be clearly formulated in an experimental protocol.  This protocol should be submitted for 
consideration, comment, guidance, and where appropriate, approval to a specially appointed 
ethical review committee, which must be independent of the investigator, the sponsor or any 
other kind of undue influence.  This independent committee should be in conformity with the 
laws and regulations of the country in which the research experiment is performed.  The 
committee has the right to monitor ongoing trials.  The researcher has the obligation to provide 
monitoring information to the committee, especially any serious adverse events.  The 
researcher should also submit to the committee, for review, information regarding funding, 
sponsors, institutional affiliations, other potential conflicts of interest and incentives for 
subjects. 
5. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in this 
Declaration. 
6. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  The 
responsibility for the human subject must always rest with a medically qualified person and 
never rest on the subject of the research, even though the subject has given consent. 
7. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the 
subject or to others.  This does not preclude the participation of healthy volunteers in 
medical research.  The design of all studies should be publicly available. 
8. Physicians should abstain from engaging in research projects involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed.  Physicians should cease any investigation if the risks are found to 
outweigh the potential benefits or if there is conclusive proof of positive and beneficial results. 
9. Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject.  This is especially important 
when the human subjects are healthy volunteers. 
10. Medical research is only justified if there is a reasonable likelihood that the populations in 
which the research is carried out stand to benefit from the results of the research. 
11. The subjects must be volunteers and informed participants in the research project. 
12. The right of research subjects to safeguard their integrity must always be respected.  Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the 
patient's information and to minimize the impact of the study on the subject's physical and 


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Page 46 
 
 
mental integrity and on the personality of the subject. 
13. In any research on human beings, each potential subject must be adequately informed of the 
aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations 
of the researcher, the anticipated benefits and potential risks of the study and the discomfort 
it may entail.  The subject should be informed of the right to abstain from participation in the 
study or to withdraw consent to participate at any time without reprisal.  After ensuring that 
the subject has understood the information, the physician should then obtain the subject's 
freely-given informed consent, preferably in writing.  If the consent cannot be obtained in 
writing, the non-written consent must be formally documented and witnessed. 
14. When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress.  In that case the informed consent should be obtained by a well-informed physician 
who is not engaged in the investigation and who is completely independent of this 
relationship. 
15. For a research subject who is legally incompetent, physically or mentally incapable of giving 
consent or is a legally incompetent minor, the investigator must obtain informed consent from 
the legally authorized representative in accordance with applicable law.  These groups should 
not be included in research unless the research is necessary to promote the health of the 
population represented and this research cannot instead be performed on legally competent 
persons. 
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition 
to the consent of the legally authorized representative. 
17. Research on individuals from whom it is not possible to obtain consent, including proxy or 
advance consent, should be done only if the physical/mental condition that prevents obtaining 
informed consent is a necessary characteristic of the research population.  The specific reasons 
for involving research subjects with a condition that renders them unable to give informed 
consent should be stated in the experimental protocol for consideration and approval of the 
review committee.  The protocol should state that consent to remain in the research should be 
obtained as soon as possible from the individual or a legally authorized surrogate. 
18. Both authors and publishers have ethical obligations.  In publication of the results of research, 
the investigators are obliged to preserve the accuracy of the results.  Negative as well as 
positive results should be published or otherwise publicly available.  Sources of funding, 
institutional affiliations and any possible conflicts of interest should be declared in the 
publication.  Reports of experimentation not in accordance with the principles laid down in 
this Declaration should not be accepted for publication. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL 
CARE 
1 
The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value.  
When medical research is combined with medical care, additional standards apply to 
protect the patients who are research subjects. 
2 
The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods.  This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 


Pro00001307 Protocol, Amendment 12 – 08Nov2019  
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Page 47 
 
 
diagnostic or therapeutic method exists. 
3 
At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by 
the study. 
4 
The physician should fully inform the patient which aspects of the care are related to the 
research.  The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship. 
5 
In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic 
measures, if in the physician's judgment it offers hope of saving life, re-establishing health 
or alleviating suffering.  Where possible, these measures should be made the object of 
research, designed to evaluate their safety and efficacy.  In all cases, new information 
should be recorded and, where appropriate, published.  The other relevant guidelines of 
this Declaration should be followed. 


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6 
Common Terminology Criteria for Adverse Events 3.0 
http://ctep.cancer.gov/reporting/ctc.html  
 


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7 
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