Study of DOXIL/CAELYX (Pegylated Liposomal Doxorubicin) and VELCADE (Bortezomib) or VELCADE Monotherapy for the Treatment of Relapsed Multiple Myeloma

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00103506
• Collaborator: (none)
• Enrollment: 646
• Locations: 109
• Arms: 2
• Duration (Months): 114
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate time to progression, overall survival, response rate and safety for the two open-label treatment groups; DOXIL/CAELYX in combination with VELCADE vs. VELCADE monotherapy.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Bortezomib (VELCADE); Drug: Bortezomib (VELCADE); Drug: Doxorubicin hydrochloride (DOXIL/CAELYX)	Phase 3

Detailed Description

This is a randomized (study drug assigned by chance), parallel-group, open-label (all involved people know the identity of the intervention), multicenter study in 18 countries. A total of 646 patients with multiple myeloma whose disease has progressed after an initial response to at least 1 line of prior therapy or was refractory to initial treatment will be enrolled. The primary endpoint is time to progression (the interval between the date of randomization and the date of disease progression); secondary endpoints are overall survival (the interval between the date of randomization and the patient's death from any cause), response rate (the proportion of patients in the evaluable population who achieved a complete or partial response), and safety. Other study endpoints include patient reported outcomes and exploratory pharmacogenics (to identify genetic markers of response). Patients are assessed for efficacy and safety every 3 weeks until disease progression is documented or for up to 42 weeks from the start of the first dose of study drug. Patients, who do not progress after the 42-week period, are assessed every 6 weeks until disease progression is documented. Efficacy evaluations includes: serum protein electrophoresis, 24-hour urine collection for protein electrophoresis, skeletal survey (plain films), bone marrow biopsy and aspirate, clinical or radiologic assessment of plasmacytomas, and serum calcium. Responses and progressions are assessed objectively by a computer algorithm based on the EBMT criteria. Safety evaluations include adverse event reports, changes in clinical laboratory findings, and tests for cardiac function (multiple gated acquisition scan/echocardiogram and electrocardiogram). Group A: VELCADE monotherapy: VELCADE 1.3 milligram per meter square (mg/m^{2) to be administered by i.v. bolus on Days 1, 4, 8, and 11 of each 21-day cycle. Group B: DOXIL/VELCADE combination: treated with VELCADE at the same dose and schedule as specified in Group A. DOXIL/CAELYX 30 mg/m}2 by intravenous infusion given on Day 4 of every 21-day cycle following the administration of VELCADE.

Study Design

• Study Type: Interventional
• Actual Enrollment: 646 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Controlled Study of DOXIL/CAELYX (Doxorubicin HCL Liposome Injection) and VELCADE (Bortezomib) or VELCADE Monotherapy for the Treatment of Relapsed Multiple Myeloma
• Study Start Date: Dec 1, 2004
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: VELCADE (bortezomib) monotherapy Bortezomib (VELCADE) 1.3 milligram per meter square (mg/m^2) by rapid (bolus) i.v. administration given on Days 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles.	Drug: Bortezomib (VELCADE); 1.3 mg/m^2 by rapid (bolus) i.v. administration given on Days 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles.
Experimental: DOXIL/CAELYX in combination with VELCADE (bortezomib) Bortezomib (VELCADE) 1.3 mg/m^2 by rapid (bolus) i.v. administration given on Days 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. Doxorubicin hydrochloride (DOXIL/CAELYX) 30 mg/m2 by i.v. infusion will be given on Day 4 of every 21-day cycle after the administration of bortezomib (VELCADE) for up to 8 cycles.	Drug: Bortezomib (VELCADE); 1.3 mg/m^2 by rapid (bolus) i.v. administration given on Days 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles..; Drug: Doxorubicin hydrochloride (DOXIL/CAELYX); mg/m^2 by i.v. infusion will be given on Day 4 of every 21-day cycle after the administration of bortezomib (VELCADE) for up to 8 cycles.

Outcome Measures

Primary Outcome Measures

1. Time to Progression (TTP) [Up to 1 year and 4 months (From date of first participant randomization [20 December 2004] up to interim analysis cut-off date [28 April 2006])]

   Median time to progression of disease is assessed according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of >=25% from lowest level in Serum M-component or (the absolute increase must be >=0.5 gram per deciliter [g/dL]); Urine M component or (the absolute increase must be >=200 milligram per 24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase >10 mg/dL. Bone marrow plasma cell percentage >=10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing. Development of hypercalcemia. Participants who died or dropped out due to any reason without progression will be censored with the day of death or drop-out, respectively and who are alive at the end of the study without any progression was censored with the last available date.

Secondary Outcome Measures

1. Overall Survival [Up to 9 years and 5 months (From date of first participant randomization [20 December 2004] to cut-off date for final survival analysis (16 May 2014)]

   The OS is defined as the time from the date of first dose of study drug to date of death from any cause. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant will be last known to be alive.

2. Number of Participants With Serious Adverse Events (SAEs) [Up to 1 year and 11 months (From date of first participant randomization [20 December 2004] to cut-off date for safety update (28 November 2006)]

   A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with multiple myeloma who have received at least 1 prior therapy and who have either responded and later had progressive disease or have progressed during their first therapy (primary refractory) are eligible for the study

• Patients who may have received prior doxorubicin but not more than a cumulative dose of 240 milligram per meter square (mg/m^2) doxorubicin, DOXIL, or the equivalent amount of another anthracycline (i.e., 1 mg doxorubicin = 1 mg DOXIL/CAELYX = 1.8 mg epirubicin = 0.3 mg mitoxantrone = 0.25 mg idarubicin)

• Must have normal cardiac function, as evidenced by a left LVEF within institutional normal limits.

Exclusion Criteria:

• History of treatment with VELCADE or progressive disease while receiving an anthracycline-containing regimen

• No change in disease status during initial therapy

• No treatment for malignancy within past 5 yrs (other than multiple myeloma) or progressive disease while receiving anthracycline-containing regimen

• Non-secretory disease

• Myocardial infarct within past 6 months

• No major surgery in past 30 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Alabaster	Alabama	United States
2		Surprise	Arizona	United States
3		Berkeley	California	United States
4		Loma Linda	California	United States
5		Los Angeles	California	United States
6		Sacramento	California	United States
7		Norwalk	Connecticut	United States
8		Stamford	Connecticut	United States
9		Jacksonville	Florida	United States
10		Miami	Florida	United States
11		Stuart	Florida	United States
12		West Palm Beach	Florida	United States
13		Altanta	Georgia	United States
14		Boise	Idaho	United States
15		Indianapolis	Indiana	United States
16		Lexington	Kentucky	United States
17		Metairie	Louisiana	United States
18		New Orleans	Louisiana	United States
19		Minneapolis	Minnesota	United States
20		Hackensack	New Jersey	United States
21		Chapel Hill	North Carolina	United States
22		Charlotte	North Carolina	United States
23		Durham	North Carolina	United States
24		Portland	Oregon	United States
25		Philadelphia	Pennsylvania	United States
26		Pittsburgh	Pennsylvania	United States
27		N Charleston	South Carolina	United States
28		Nashville	Tennessee	United States
29		Buenos Aires		Argentina
30		Ciudad De Buenos Aires		Argentina
31		La Plata		Argentina
32		Mendoza		Argentina
33		Adelaide		Australia
34		Darlinghurst		Australia
35		Melbourne		Australia
36		Perth		Australia
37		Sydney		Australia
38		Graz		Austria
39		Innsbruck		Austria
40		Salzburg		Austria
41		Wels N/A		Austria
42		Wien		Austria
43		Brussel		Belgium
44		Gent		Belgium
45		Leuven		Belgium
46		Mont-Godinne		Belgium
47		Vancouver	British Columbia	Canada
48		Hamilton	Ontario	Canada
49		Ottawa	Ontario	Canada
50		Montreal	Quebec	Canada
51		N/a N/a		Canada
52		Quebec		Canada
53		Brno		Czech Republic
54		Olomouc		Czech Republic
55		Praha 2 N/A		Czech Republic
56		Angers Cedex 1 N/A		France
57		Bobigny		France
58		Creteil N/A		France
59		Lille Cedex N/A		France
60		Nantes N/A		France
61		Pierre Benite		France
62		Toulouse		France
63		Tours		France
64		Vandoeuvre Les Nancy		France
65		Haifa		Israel
66		Jerusalem		Israel
67		Petach Tikva		Israel
68		Ramat Gan		Israel
69		Rehovot		Israel
70		Tel Aviv		Israel
71		Amersfoort		Netherlands
72		Amsterdam Zuidoost		Netherlands
73		Amsterdam		Netherlands
74		Delft		Netherlands
75		Den Haag		Netherlands
76		Groningen		Netherlands
77		Nieuwegein		Netherlands
78		Nijmegen		Netherlands
79		Rotterdam		Netherlands
80		Utrecht		Netherlands
81		Bialystok		Poland
82		Gdansk		Poland
83		Lodz		Poland
84		Lublin		Poland
85		Warszawa		Poland
86		Wroclaw		Poland
87		Coimbra		Portugal
88		Lisboa		Portugal
89		Porto N/A		Portugal
90		Arkhangelsk		Russian Federation
91		Ekaterinburg		Russian Federation
92		Izhevsk		Russian Federation
93		Moscow N/A		Russian Federation
94		Moscow		Russian Federation
95		Nizhny Novgorod		Russian Federation
96		Novosibirsk		Russian Federation
97		Obninsk		Russian Federation
98		St. Petersburg		Russian Federation
99		Singapore		Singapore
100		Bloemfontein N/A		South Africa
101		Cape Town		South Africa
102		Johannesburg		South Africa
103		Parktown		South Africa
104		Pretoria Gauteng		South Africa
105		Barcelona		Spain
106		Madrid		Spain
107		Salamanca		Spain
108		Bath		United Kingdom
109		London		United Kingdom

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC C. Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT00103506
• Other Study ID Numbers: CR004117; DOXILMMY3001; 2004-001842-34
• First Posted: Feb 10, 2005
• Last Update Posted: Oct 19, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by Janssen Research & Development, LLC: Multiple Myeloma; Doxil; Caelyx; Doxorubicin; Velcade; Bortezomib
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Doxorubicin; Liposomal doxorubicin; Bortezomib

Study Results

Participant Flow

Arm/Group Title	Velcade (Bortezomib) Monotherapy	Doxil/Caelyx Plus Velcade (Bortezomib)
Arm/Group Description	Velcade (bortezomib) 1.3 milligram/meter per square (mg/m^2) by rapid (bolus) intravenous (IV) administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles.	Velcade (bortezomib) 1.3 mg/m^2 by rapid (bolus) IV administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. Doxorubicin hydrochloride (DOXIL/CAELYX) 30 mg/m^2 by IV infusion will be given on Day 4 of every 21-day cycle after the administration of VELCADE (bortezomib) up to 8 cycles.
Period Title: Overall Study
STARTED	322	324
COMPLETED	0	0
NOT COMPLETED	322	324

Baseline Characteristics

Arm/Group Title	Velcade (Bortezomib) Monotherapy	Doxil/Caelyx Plus Velcade (Bortezomib)	Total
Arm/Group Description	Velcade (bortezomib) 1.3 milligram/meter per square (mg/m^2) by rapid (bolus) intravenous (IV) administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles.	Velcade (bortezomib) 1.3 mg/m^2 by rapid (bolus) IV administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. Doxorubicin hydrochloride (DOXIL/CAELYX) 30 mg/m^2 by IV infusion will be given on Day 4 of every 21-day cycle after the administration of VELCADE (bortezomib) up to 8 cycles.	Total of all reporting groups
Overall Participants	322	324	646
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.5 (9.56)	61.4 (9.61)	61.4 (9.58)
Sex: Female, Male (Count of Participants)
Female	148 46%	135 41.7%	283 43.8%
Male	174 54%	189 58.3%	363 56.2%
Region of Enrollment (participants) [Number]
ARGENTINA	6 1.9%	9 2.8%	15 2.3%
AUSTRALIA	31 9.6%	31 9.6%	62 9.6%
AUSTRIA	12 3.7%	6 1.9%	18 2.8%
BELGIUM-LUXEMBURG	6 1.9%	14 4.3%	20 3.1%
CANADA	20 6.2%	23 7.1%	43 6.7%
CZECH REPUBLIC	14 4.3%	22 6.8%	36 5.6%
FRANCE	21 6.5%	28 8.6%	49 7.6%
GREAT BRITAIN	8 2.5%	7 2.2%	15 2.3%
ISRAEL	25 7.8%	21 6.5%	46 7.1%
ITALY	17 5.3%	11 3.4%	28 4.3%
NETHERLANDS	29 9%	32 9.9%	61 9.4%
POLAND	35 10.9%	17 5.2%	52 8%
PORTUGAL	6 1.9%	14 4.3%	20 3.1%
RUSSIA	38 11.8%	34 10.5%	72 11.1%
SINGAPORE	3 0.9%	2 0.6%	5 0.8%
SOUTH AFRICA	13 4%	15 4.6%	28 4.3%
SPAIN	20 6.2%	15 4.6%	35 5.4%
UNITED STATES OF AMERICA	18 5.6%	23 7.1%	41 6.3%

Outcome Measures

1. Primary Outcome

Title	Time to Progression (TTP)
Description	Median time to progression of disease is assessed according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of >=25% from lowest level in Serum M-component or (the absolute increase must be >=0.5 gram per deciliter [g/dL]); Urine M component or (the absolute increase must be >=200 milligram per 24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase >10 mg/dL. Bone marrow plasma cell percentage >=10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing. Development of hypercalcemia. Participants who died or dropped out due to any reason without progression will be censored with the day of death or drop-out, respectively and who are alive at the end of the study without any progression was censored with the last available date.
Time Frame	Up to 1 year and 4 months (From date of first participant randomization [20 December 2004] up to interim analysis cut-off date [28 April 2006])

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) included all the randomized participants.

Arm/Group Title	Velcade (Bortezomib) Monotherapy	Doxil/Caelyx Plus Velcade (Bortezomib)
Arm/Group Description	Velcade (bortezomib) 1.3 milligram/meter per square (mg/m^2) by rapid (bolus) intravenous (IV) administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles.	Velcade (bortezomib) 1.3 mg/m^2 by rapid (bolus) IV administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. Doxorubicin hydrochloride (DOXIL/CAELYX) 30 mg/m^2 by IV infusion will be given on Day 4 of every 21-day cycle after the administration of VELCADE (bortezomib) up to 8 cycles.
Measure Participants	322	324
Median (95% Confidence Interval) [Months]	6.5	9.3

2. Secondary Outcome

Title	Overall Survival
Description	The OS is defined as the time from the date of first dose of study drug to date of death from any cause. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant will be last known to be alive.
Time Frame	Up to 9 years and 5 months (From date of first participant randomization [20 December 2004] to cut-off date for final survival analysis (16 May 2014)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Velcade (Bortezomib) Monotherapy	Doxil/Caelyx Plus Velcade (Bortezomib)
Arm/Group Description	Velcade (bortezomib) 1.3 milligram/meter per square (mg/m^2) by rapid (bolus) intravenous (IV) administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles.	Velcade (bortezomib) 1.3 mg/m^2 by rapid (bolus) IV administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. Doxorubicin hydrochloride (DOXIL/CAELYX) 30 mg/m^2 by IV infusion will be given on Day 4 of every 21-day cycle after the administration of VELCADE (bortezomib) up to 8 cycles.
Measure Participants	322	324
Median (95% Confidence Interval) [months]	30.8	33.0

3. Secondary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs)
Description	A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time Frame	Up to 1 year and 11 months (From date of first participant randomization [20 December 2004] to cut-off date for safety update (28 November 2006)

Outcome Measure Data

Analysis Population Description

Safety population included all the participants who received at least one dose of study drug. Here 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Velcade (Bortezomib) Monotherapy	Doxil/Caelyx Plus Velcade (Bortezomib)
Arm/Group Description	Velcade (bortezomib) 1.3 milligram/meter per square (mg/m^2) by rapid (bolus) intravenous (IV) administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles.	Velcade (bortezomib) 1.3 mg/m^2 by rapid (bolus) IV administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. Doxorubicin hydrochloride (DOXIL/CAELYX) 30 mg/m^2 by IV infusion will be given on Day 4 of every 21-day cycle after the administration of VELCADE (bortezomib) up to 8 cycles.
Measure Participants	318	318
Number [Participants]	105 32.6%	120 37%

Adverse Events

Adverse Event Reporting Description	Safety population included all the participants who received at least one dose of study drug.
Arm/Group Title	Velcade (Bortezomib) Monotherapy		Doxil/Caelyx Plus Velcade (Bortezomib)
Arm/Group Description	Velcade (bortezomib) 1.3 milligram/meter per square (mg/m^2) by rapid (bolus) intravenous (IV) administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles.		Velcade (bortezomib) 1.3 mg/m^2 by rapid (bolus) IV administration given on Day 1, 4, 8, and 11 of each 21-day cycle for up to 8 cycles. Doxorubicin hydrochloride (DOXIL/CAELYX) 30 mg/m^2 by IV infusion will be given on Day 4 of every 21-day cycle after the administration of VELCADE (bortezomib) up to 8 cycles.
All Cause Mortality
	Velcade (Bortezomib) Monotherapy		Doxil/Caelyx Plus Velcade (Bortezomib)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Velcade (Bortezomib) Monotherapy		Doxil/Caelyx Plus Velcade (Bortezomib)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	105/318 (33%)		120/318 (37.7%)
Blood and lymphatic system disorders
Anaemia	4/318 (1.3%)		3/318 (0.9%)
Febrile Neutropenia	2/318 (0.6%)		5/318 (1.6%)
Leukopenia	0/318 (0%)		1/318 (0.3%)
Neutropenia	0/318 (0%)		2/318 (0.6%)
Pancytopenia	0/318 (0%)		2/318 (0.6%)
Thrombocytopenia	0/318 (0%)		9/318 (2.8%)
Cardiac disorders
Acute Myocardial Infarction	0/318 (0%)		1/318 (0.3%)
Angina Pectoris	1/318 (0.3%)		0/318 (0%)
Angina Unstable	1/318 (0.3%)		0/318 (0%)
Arrhythmia	1/318 (0.3%)		0/318 (0%)
Atrial Fibrillation	2/318 (0.6%)		0/318 (0%)
Atrial Flutter	0/318 (0%)		1/318 (0.3%)
Cardiac Arrest	0/318 (0%)		1/318 (0.3%)
Cardiac Failure	2/318 (0.6%)		0/318 (0%)
Cardiac Failure Chronic	0/318 (0%)		1/318 (0.3%)
Cardiac Failure Congestive	2/318 (0.6%)		2/318 (0.6%)
Cardio-Respiratory Arrest	1/318 (0.3%)		0/318 (0%)
Myocardial Infarction	1/318 (0.3%)		2/318 (0.6%)
Nodal Arrhythmia	0/318 (0%)		1/318 (0.3%)
Right Ventricular Failure	1/318 (0.3%)		1/318 (0.3%)
Tachyarrhythmia	0/318 (0%)		1/318 (0.3%)
Ear and labyrinth disorders
Deafness	0/318 (0%)		1/318 (0.3%)
Vertigo	3/318 (0.9%)		0/318 (0%)
Endocrine disorders
Adrenal Insufficiency	0/318 (0%)		1/318 (0.3%)
Hypercorticoidism	0/318 (0%)		1/318 (0.3%)
Inappropriate Antidiuretic Hormone Secretion	1/318 (0.3%)		0/318 (0%)
Eye disorders
Cataract	0/318 (0%)		1/318 (0.3%)
Corneal Erosion	0/318 (0%)		1/318 (0.3%)
Diplopia	1/318 (0.3%)		0/318 (0%)
Retinal Vein Thrombosis	1/318 (0.3%)		0/318 (0%)
Gastrointestinal disorders
Abdominal Pain	2/318 (0.6%)		2/318 (0.6%)
Diarrhoea	6/318 (1.9%)		7/318 (2.2%)
Dyspepsia	0/318 (0%)		1/318 (0.3%)
Dysphagia	0/318 (0%)		2/318 (0.6%)
Faecaloma	0/318 (0%)		1/318 (0.3%)
Flatulence	1/318 (0.3%)		0/318 (0%)
Gastric Ulcer	0/318 (0%)		2/318 (0.6%)
Gastroduodenal Haemorrhage	0/318 (0%)		1/318 (0.3%)
Gastrointestinal Haemorrhage	1/318 (0.3%)		3/318 (0.9%)
Gastrooesophageal Reflux Disease	0/318 (0%)		1/318 (0.3%)
Haematemesis	2/318 (0.6%)		2/318 (0.6%)
Ileus	0/318 (0%)		1/318 (0.3%)
Ileus Paralytic	1/318 (0.3%)		1/318 (0.3%)
Large Intestine Perforation	0/318 (0%)		1/318 (0.3%)
Mallory-Weiss Syndrome	0/318 (0%)		2/318 (0.6%)
Nausea	3/318 (0.9%)		7/318 (2.2%)
Rectal Haemorrhage	0/318 (0%)		1/318 (0.3%)
Rectal Prolapse	1/318 (0.3%)		0/318 (0%)
Small Intestinal Obstruction	1/318 (0.3%)		1/318 (0.3%)
Stomatitis	0/318 (0%)		1/318 (0.3%)
Upper Gastrointestinal Haemorrhage	0/318 (0%)		2/318 (0.6%)
Vomiting	2/318 (0.6%)		13/318 (4.1%)
General disorders
Asthenia	1/318 (0.3%)		2/318 (0.6%)
Catheter Related Complication	1/318 (0.3%)		0/318 (0%)
Chest Pain	3/318 (0.9%)		0/318 (0%)
Chills	1/318 (0.3%)		0/318 (0%)
Death	1/318 (0.3%)		0/318 (0%)
Fatigue	0/318 (0%)		3/318 (0.9%)
General Physical Health Deterioration	0/318 (0%)		1/318 (0.3%)
Hyperthermia	1/318 (0.3%)		0/318 (0%)
Influenza Like Illness	0/318 (0%)		1/318 (0.3%)
Multi-Organ Failure	0/318 (0%)		1/318 (0.3%)
Oedema Peripheral	1/318 (0.3%)		0/318 (0%)
Pain	0/318 (0%)		1/318 (0.3%)
Pyrexia	8/318 (2.5%)		15/318 (4.7%)
Sudden Cardiac Death	1/318 (0.3%)		0/318 (0%)
Sudden Death	0/318 (0%)		1/318 (0.3%)
Immune system disorders
Hypersensitivity	0/318 (0%)		1/318 (0.3%)
Infections and infestations
Abdominal Infection	0/318 (0%)		1/318 (0.3%)
Bacterial Sepsis	1/318 (0.3%)		0/318 (0%)
Bronchitis	1/318 (0.3%)		0/318 (0%)
Bronchitis Acute	2/318 (0.6%)		0/318 (0%)
Bronchitis Chronic	2/318 (0.6%)		0/318 (0%)
Bronchopneumonia	1/318 (0.3%)		3/318 (0.9%)
Candidiasis	0/318 (0%)		1/318 (0.3%)
Catheter Related Infection	0/318 (0%)		2/318 (0.6%)
Cellulitis	1/318 (0.3%)		1/318 (0.3%)
Diarrhoea Infectious	1/318 (0.3%)		0/318 (0%)
Ear Infection	0/318 (0%)		1/318 (0.3%)
Furuncle	0/318 (0%)		1/318 (0.3%)
Gastroenteritis	3/318 (0.9%)		1/318 (0.3%)
Genitourinary Tract Infection	1/318 (0.3%)		0/318 (0%)
Herpes Zoster	3/318 (0.9%)		5/318 (1.6%)
Herpes Zoster Disseminated	1/318 (0.3%)		1/318 (0.3%)
Infection	1/318 (0.3%)		1/318 (0.3%)
Klebsiella Sepsis	1/318 (0.3%)		0/318 (0%)
Laryngitis	1/318 (0.3%)		0/318 (0%)
Lobar Pneumonia	1/318 (0.3%)		0/318 (0%)
Lower Respiratory Tract Infection	3/318 (0.9%)		3/318 (0.9%)
Meningitis Bacterial	1/318 (0.3%)		0/318 (0%)
Neutropenic Sepsis	0/318 (0%)		1/318 (0.3%)
Opportunistic Infection	0/318 (0%)		1/318 (0.3%)
Orchitis	0/318 (0%)		1/318 (0.3%)
Osteomyelitis	0/318 (0%)		1/318 (0.3%)
Pneumococcal Bacteraemia	0/318 (0%)		1/318 (0.3%)
Pneumococcal Sepsis	1/318 (0.3%)		2/318 (0.6%)
Pneumocystis JiroveCI Pneumonia	0/318 (0%)		1/318 (0.3%)
Pneumonia	20/318 (6.3%)		16/318 (5%)
Pneumonia Aspergillus	1/318 (0.3%)		0/318 (0%)
Pneumonia Legionella	0/318 (0%)		1/318 (0.3%)
Pneumonia Pneumococcal	0/318 (0%)		1/318 (0.3%)
Pseudomonas Infection	0/318 (0%)		2/318 (0.6%)
Respiratory Tract Infection	2/318 (0.6%)		3/318 (0.9%)
Respiratory Tract Infection Bacterial	0/318 (0%)		1/318 (0.3%)
Sepsis	0/318 (0%)		1/318 (0.3%)
Septic Embolus	0/318 (0%)		1/318 (0.3%)
Septic Shock	1/318 (0.3%)		3/318 (0.9%)
Sinusitis	1/318 (0.3%)		0/318 (0%)
Skin Infection	1/318 (0.3%)		0/318 (0%)
Staphylococcal Sepsis	0/318 (0%)		2/318 (0.6%)
Upper Respiratory Tract Infection	2/318 (0.6%)		4/318 (1.3%)
Urinary Tract Infection	2/318 (0.6%)		0/318 (0%)
Urosepsis	1/318 (0.3%)		0/318 (0%)
Injury, poisoning and procedural complications
Drug Toxicity	0/318 (0%)		1/318 (0.3%)
Fall	1/318 (0.3%)		1/318 (0.3%)
Skeletal Injury	0/318 (0%)		1/318 (0.3%)
Spinal Compression Fracture	0/318 (0%)		1/318 (0.3%)
Thoracic Vertebral Fracture	1/318 (0.3%)		0/318 (0%)
Investigations
Blood Creatinine Increased	2/318 (0.6%)		3/318 (0.9%)
Blood Glucose Increased	0/318 (0%)		1/318 (0.3%)
Ejection Fraction Decreased	0/318 (0%)		2/318 (0.6%)
Troponin I Increased	1/318 (0.3%)		0/318 (0%)
Metabolism and nutrition disorders
Anorexia	0/318 (0%)		2/318 (0.6%)
Dehydration	6/318 (1.9%)		6/318 (1.9%)
Gout	0/318 (0%)		1/318 (0.3%)
Hypercalcaemia	1/318 (0.3%)		1/318 (0.3%)
Hyperkalaemia	1/318 (0.3%)		0/318 (0%)
Hypoalbuminaemia	1/318 (0.3%)		1/318 (0.3%)
Hypoglycaemia	1/318 (0.3%)		0/318 (0%)
Hypokalaemia	1/318 (0.3%)		3/318 (0.9%)
Hyponatraemia	1/318 (0.3%)		1/318 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/318 (0.6%)		0/318 (0%)
Back Pain	3/318 (0.9%)		0/318 (0%)
Bone Lesion	1/318 (0.3%)		1/318 (0.3%)
Bone Pain	1/318 (0.3%)		1/318 (0.3%)
Bursitis	0/318 (0%)		1/318 (0.3%)
Joint Instability	0/318 (0%)		1/318 (0.3%)
Musculoskeletal Chest Pain	0/318 (0%)		1/318 (0.3%)
Myalgia	1/318 (0.3%)		0/318 (0%)
Osteonecrosis	0/318 (0%)		1/318 (0.3%)
Pain in Extremity	2/318 (0.6%)		0/318 (0%)
Pathological Fracture	0/318 (0%)		2/318 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer Pain	1/318 (0.3%)		0/318 (0%)
Colon Cancer	0/318 (0%)		1/318 (0.3%)
Tumour Lysis Syndrome	1/318 (0.3%)		2/318 (0.6%)
Nervous system disorders
Autonomic Neuropathy	1/318 (0.3%)		0/318 (0%)
Balance Disorder	1/318 (0.3%)		0/318 (0%)
Cauda Equina Syndrome	2/318 (0.6%)		1/318 (0.3%)
Cerebral Haemorrhage	0/318 (0%)		1/318 (0.3%)
Cerebral Infarction	0/318 (0%)		1/318 (0.3%)
Cerebral Ischaemia	0/318 (0%)		1/318 (0.3%)
Coordination Abnormal	0/318 (0%)		1/318 (0.3%)
Dizziness	1/318 (0.3%)		2/318 (0.6%)
Lumbar Radiculopathy	1/318 (0.3%)		0/318 (0%)
Neuralgia	1/318 (0.3%)		0/318 (0%)
Neuropathy	1/318 (0.3%)		0/318 (0%)
Neuropathy Peripheral	1/318 (0.3%)		2/318 (0.6%)
Paralysis	1/318 (0.3%)		0/318 (0%)
Paraparesis	1/318 (0.3%)		0/318 (0%)
Paraplegia	1/318 (0.3%)		0/318 (0%)
Polyneuropathy	1/318 (0.3%)		1/318 (0.3%)
Polyneuropathy in Malignant Disease	1/318 (0.3%)		0/318 (0%)
Quadriparesis	1/318 (0.3%)		0/318 (0%)
Spinal Cord Compression	0/318 (0%)		3/318 (0.9%)
Syncope	4/318 (1.3%)		4/318 (1.3%)
Tremor	0/318 (0%)		1/318 (0.3%)
Psychiatric disorders
Agitation	1/318 (0.3%)		0/318 (0%)
Anxiety	1/318 (0.3%)		0/318 (0%)
Completed Suicide	1/318 (0.3%)		0/318 (0%)
Nervousness	1/318 (0.3%)		0/318 (0%)
Suicidal Ideation	1/318 (0.3%)		0/318 (0%)
Renal and urinary disorders
Calculus Bladder	0/318 (0%)		1/318 (0.3%)
Haematuria	0/318 (0%)		1/318 (0.3%)
Nephritis Interstitial	1/318 (0.3%)		0/318 (0%)
Renal Colic	0/318 (0%)		1/318 (0.3%)
Renal Failure	2/318 (0.6%)		3/318 (0.9%)
Renal Failure Acute	5/318 (1.6%)		4/318 (1.3%)
Renal Failure Chronic	1/318 (0.3%)		0/318 (0%)
Renal Impairment	2/318 (0.6%)		0/318 (0%)
Urinary Bladder Haemorrhage	0/318 (0%)		1/318 (0.3%)
Urinary Retention	2/318 (0.6%)		1/318 (0.3%)
Reproductive system and breast disorders
Benign Prostatic Hyperplasia	0/318 (0%)		1/318 (0.3%)
Epididymitis	1/318 (0.3%)		0/318 (0%)
Respiratory, thoracic and mediastinal disorders
Acute Pulmonary Oedema	1/318 (0.3%)		2/318 (0.6%)
Chronic Obstructive Pulmonary Disease	1/318 (0.3%)		0/318 (0%)
Dyspnoea	6/318 (1.9%)		2/318 (0.6%)
Dyspnoea Exertional	0/318 (0%)		1/318 (0.3%)
Interstitial Lung Disease	1/318 (0.3%)		0/318 (0%)
Pneumonitis	0/318 (0%)		2/318 (0.6%)
Pulmonary Embolism	2/318 (0.6%)		2/318 (0.6%)
Pulmonary Fibrosis	1/318 (0.3%)		0/318 (0%)
Pulmonary Hypertension	0/318 (0%)		2/318 (0.6%)
Pulmonary Oedema	0/318 (0%)		1/318 (0.3%)
Respiratory Failure	1/318 (0.3%)		1/318 (0.3%)
Skin and subcutaneous tissue disorders
Epidermal Necrosis	0/318 (0%)		1/318 (0.3%)
Jessner's Lymphocytic Infiltration	1/318 (0.3%)		0/318 (0%)
Palmar-Plantar Erythrodysaesthesia Syndrome	0/318 (0%)		1/318 (0.3%)
Rash	0/318 (0%)		1/318 (0.3%)
Swelling Face	1/318 (0.3%)		0/318 (0%)
Vascular disorders
Deep Vein Thrombosis	1/318 (0.3%)		0/318 (0%)
Hypotension	2/318 (0.6%)		4/318 (1.3%)
Orthostatic Hypotension	2/318 (0.6%)		2/318 (0.6%)
Phlebitis	0/318 (0%)		1/318 (0.3%)
Thrombophlebitis	0/318 (0%)		1/318 (0.3%)
Other (Not Including Serious) Adverse Events
	Velcade (Bortezomib) Monotherapy		Doxil/Caelyx Plus Velcade (Bortezomib)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	299/318 (94%)		313/318 (98.4%)
Blood and lymphatic system disorders
Anaemia	67/318 (21.1%)		80/318 (25.2%)
Leukopenia	23/318 (7.2%)		28/318 (8.8%)
Neutropenia	71/318 (22.3%)		113/318 (35.5%)
Thrombocytopenia	89/318 (28%)		104/318 (32.7%)
Eye disorders
Conjunctivitis	17/318 (5.3%)		24/318 (7.5%)
Gastrointestinal disorders
Abdominal Pain	23/318 (7.2%)		32/318 (10.1%)
Abdominal Pain Upper	13/318 (4.1%)		24/318 (7.5%)
Constipation	98/318 (30.8%)		99/318 (31.1%)
Diarrhoea	122/318 (38.4%)		142/318 (44.7%)
Dyspepsia	13/318 (4.1%)		27/318 (8.5%)
Nausea	125/318 (39.3%)		152/318 (47.8%)
Stomatitis	11/318 (3.5%)		55/318 (17.3%)
Vomiting	67/318 (21.1%)		93/318 (29.2%)
General disorders
Asthenia	56/318 (17.6%)		70/318 (22%)
Chills	18/318 (5.7%)		25/318 (7.9%)
Fatigue	88/318 (27.7%)		115/318 (36.2%)
Influenza Like Illness	13/318 (4.1%)		18/318 (5.7%)
Oedema Peripheral	27/318 (8.5%)		32/318 (10.1%)
Pyrexia	67/318 (21.1%)		91/318 (28.6%)
Infections and infestations
Bronchitis	14/318 (4.4%)		25/318 (7.9%)
Herpes Simplex	18/318 (5.7%)		32/318 (10.1%)
Herpes Zoster	26/318 (8.2%)		30/318 (9.4%)
Nasopharyngitis	20/318 (6.3%)		25/318 (7.9%)
Pneumonia	9/318 (2.8%)		18/318 (5.7%)
Upper Respiratory Tract Infection	32/318 (10.1%)		30/318 (9.4%)
Investigations
Aspartate Aminotransferase Increased	11/318 (3.5%)		16/318 (5%)
Blood Creatinine Increased	7/318 (2.2%)		16/318 (5%)
Weight Decreased	12/318 (3.8%)		37/318 (11.6%)
Metabolism and nutrition disorders
Anorexia	43/318 (13.5%)		58/318 (18.2%)
Decreased Appetite	9/318 (2.8%)		30/318 (9.4%)
Hypocalcaemia	9/318 (2.8%)		19/318 (6%)
Hypokalaemia	15/318 (4.7%)		23/318 (7.2%)
Hypomagnesaemia	12/318 (3.8%)		17/318 (5.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	27/318 (8.5%)		34/318 (10.7%)
Back Pain	37/318 (11.6%)		38/318 (11.9%)
Bone Pain	25/318 (7.9%)		10/318 (3.1%)
Musculoskeletal Chest Pain	12/318 (3.8%)		20/318 (6.3%)
Myalgia	20/318 (6.3%)		10/318 (3.1%)
Pain in Extremity	47/318 (14.8%)		34/318 (10.7%)
Nervous system disorders
Dizziness	27/318 (8.5%)		32/318 (10.1%)
Dysgeusia	9/318 (2.8%)		18/318 (5.7%)
Headache	56/318 (17.6%)		59/318 (18.6%)
Neuralgia	63/318 (19.8%)		54/318 (17%)
Neuropathy	38/318 (11.9%)		35/318 (11%)
Neuropathy Peripheral	46/318 (14.5%)		36/318 (11.3%)
Paraesthesia	31/318 (9.7%)		41/318 (12.9%)
Peripheral Sensory Neuropathy	42/318 (13.2%)		41/318 (12.9%)
Polyneuropathy	27/318 (8.5%)		26/318 (8.2%)
Psychiatric disorders
Depression	16/318 (5%)		9/318 (2.8%)
Insomnia	43/318 (13.5%)		35/318 (11%)
Respiratory, thoracic and mediastinal disorders
Cough	38/318 (11.9%)		58/318 (18.2%)
Dyspnoea	22/318 (6.9%)		32/318 (10.1%)
Epistaxis	12/318 (3.8%)		18/318 (5.7%)
Skin and subcutaneous tissue disorders
Dry Skin	7/318 (2.2%)		28/318 (8.8%)
Palmar-Plantar Erythrodysaesthesia Syndrome	1/318 (0.3%)		62/318 (19.5%)
Pruritus	16/318 (5%)		20/318 (6.3%)
Rash	29/318 (9.1%)		48/318 (15.1%)
Vascular disorders
Hypertension	17/318 (5.3%)		15/318 (4.7%)

Limitations/Caveats

Study stopped in terms of primary endpoint based on its results at planned interim analysis (28 Apr 2006). However, Long-term follow-up for survival continued until 16 May 2014.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

A copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested in writing, such publication will be withheld for up to an additional 60 days.