A Study of Subcutaneous and Intravenous VELCADE in Patients With Previously Treated Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT00722566

Recruitment Status : Completed

First Posted : July 25, 2008

Results First Posted : October 4, 2011

Last Update Posted : October 10, 2011

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Sponsor:

Collaborator:

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Information provided by (Responsible Party):

Millennium Pharmaceuticals, Inc.

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Multiple Myeloma
Interventions	Drug: VELCADE Administered by subcutaneous injection Drug: VELCADE Administered by intravenous infusion
Enrollment	222

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	VELCADE Subcutaneous	VELCADE Intravenous
Arm/Group Description	VELCADE 1.3 mg/m^2 administered by ...	VELCADE 1.3 mg/m^2 administered by ...
Arm/Group Description	VELCADE 1.3 mg/m^2 administered by subcutaneous injection on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles.	VELCADE 1.3 mg/m^2 administered by intravenous infusion on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles.
Period Title: Overall Study
Started	148 ^[1]	74
Completed	81 ^[2]	39 ^[2]
Not Completed	67	35
[1] One patient randomized and not dosed [2] Completed 8 cycles

Baseline Characteristics

Arm/Group Title		VELCADE Subcutaneous	VELCADE Intravenous	Total
Arm/Group Description		VELCADE 1.3 mg/m^2 administered by ...	VELCADE 1.3 mg/m^2 administered by ...	Total of all reporting groups
Arm/Group Description		VELCADE 1.3 mg/m^2 administered by subcutaneous injection on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles.	VELCADE 1.3 mg/m^2 administered by intravenous infusion on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles.	Total of all reporting groups
Overall Number of Baseline Participants		148	74	222
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	148 participants	74 participants	222 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	74 50.0%	37 50.0%	111 50.0%
	>=65 years	74 50.0%	37 50.0%	111 50.0%
Age Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	148 participants	74 participants	222 participants
		64.3 (8.96)	64.0 (12.11)	64.2 (10.09)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	148 participants	74 participants	222 participants
	Female	74 50.0%	27 36.5%	101 45.5%
	Male	74 50.0%	47 63.5%	121 54.5%
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	148 participants	74 participants	222 participants
France		22	14	36
Belgium		7	5	12
Germany		2	4	6
Netherlands		6	4	10
United Kingdom		6	3	9
Ukraine		51	17	68
Russian Federation		26	9	35
Poland		20	7	27
Argentina		5	8	13
India		3	3	6

Outcome Measures

1.Primary Outcome


Title	Number of Patients With Overall Response (Complete Response + Partial Response)
Description	Disease response was measured according to European Group for Blood an...
Description	Disease response was measured according to European Group for Blood and Marrow Transplantation (EBMT) criteria with the addition of the response categories of nCR and VGPR. Complete response requires disappearance of monoclonal protein from the blood and urine and <5% plasma cells in the bone marrow on at least 2 determinations for a minimum of 6 weeks. Partial Response requires ≥50% reduction in serum m-protein for at least 2 determinations at least 6 weeks apart and if present, reduction in 24-hour urinary light chain excretion by either ≥90% or to <200 mg
Time Frame	Over 4 cycles (prior to the addition of dexamethasone)

Outcome Measure Data

Analysis Population Description

The response-evaluable population was defined as subjects who received at least 1 dose of study drug and had measurable, secretory multiple myeloma, defined as a serum monoclonal IgG or IgM of ≥10 g/L or a serum monoclonal IgA or IgE ≥5 g/L, or a serum monoclonal IgD of ≥0.5g/L, or urine M-protein of ≥200 mg/24 hours, at study entry.


Arm/Group Title	VELCADE Subcutaneuous	VELCADE Intravenous
Arm/Group Description:	VELCADE 1.3 mg/m^2 administered by ...	VELCADE 1.3 mg/m^2 administered by ...
Arm/Group Description:	VELCADE 1.3 mg/m^2 administered by subcutaneous injection on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles.	VELCADE 1.3 mg/m^2 administered by intravenous injection on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles.
Overall Number of Participants Analyzed	145	73
Measure Type: Number Unit of Measure: Participants
	61	31

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VELCADE Subcutaneuous, VELCADE Intravenous
	Comments	In this trial, non-inferiority is defined as retaining 60% of the IV (active control) treatment effect as measured by ORR. The non-inferiority hypothesis can be stated as: H0: ORRSC - 0.60 ORRIV <0 vs. H1: ORRSC - 0.60 ORRIV ≥0 (non-inferiority).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Assuming ORRs are 35.5% for both SC and IV, one-sided alpha level of 0.025, and approximately 80% power, approximately 216 subjects (144 SC:72 IV) are needed to show non-inferiority of SC to IV VELCADE.

Statistical Test of Hypothesis	P-Value	0.00201
	Comments	[Not Specified]
	Method	Farrrington and Manning
	Comments	CONOR P. FARRINGTON AND GODFREY MANNING STATISTICS IN MEDICINE, VOL. 9, 1447-1454(1990).

Method of Estimation	Estimation Parameter	ORR_SQ - 0.6 ORR_IV
	Estimated Value	16.8
	Confidence Interval	(2-Sided) 95% 6.1 to 27.1
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Number of Patients With Complete Response
Description	Disease response was measured according to European Group for Blood an...
Description	Disease response was measured according to European Group for Blood and Marrow Transplantation (EBMT) criteria with the addition of the response categories of nCR and VGPR. Complete response requires disappearance of monoclonal protein from the blood and urine and <5% plasma cells in the bone marrow on at least 2 determinations for a minimum of 6 weeks.
Time Frame	Over 4 cycles (prior to the addition of dexamethasone)

Outcome Measure Data

Analysis Population Description


Arm/Group Title	VELCADE Subcutaneous	VELCADE Intravenous
Arm/Group Description:	VELCADE 1.3 mg/m^2 administered by ...	VELCADE 1.3 mg/m^2 administered by ...
Arm/Group Description:	VELCADE 1.3 mg/m^2 administered by subcutaneous injection on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles.	VELCADE 1.3 mg/m^2 administered by intravenous infusion on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles.
Overall Number of Participants Analyzed	145	73
Measure Type: Number Unit of Measure: Participants
	9	6

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	VELCADE Subcutaneous	VELCADE Intravenous
Arm/Group Description	VELCADE 1.3 mg/m^2 administered by ...	VELCADE 1.3 mg/m^2 administered by ...
Arm/Group Description	VELCADE 1.3 mg/m^2 administered by subcutaneous injection on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles.	VELCADE 1.3 mg/m^2 administered by intravenous infusion on Days 1, 4, 8, and 11 of a 3-week cycle for 8 cycles.
All-Cause Mortality
	VELCADE Subcutaneous	VELCADE Intravenous
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	VELCADE Subcutaneous	VELCADE Intravenous
	Affected / at Risk (%)	Affected / at Risk (%)
Total	53/147 (36.05%)	26/74 (35.14%)
Blood and lymphatic system disorders
Anemia ^† 1	0/147 (0.00%)	1/74 (1.35%)
Neutropenia ^† 1	1/147 (0.68%)	1/74 (1.35%)
Splenomegaly ^† 1	1/147 (0.68%)	0/74 (0.00%)
Thrombocytopenia ^† 1	1/147 (0.68%)	1/74 (1.35%)
Cardiac disorders
Angina Pectoris ^† 1	1/147 (0.68%)	0/74 (0.00%)
Arrhythmia ^† 1	1/147 (0.68%)	0/74 (0.00%)
Arteriosclerosis coronary artery ^† 1	1/147 (0.68%)	0/74 (0.00%)
Atrial Fibrillation ^† 1	2/147 (1.36%)	0/74 (0.00%)
Bradyarrhythmia ^† 1	1/147 (0.68%)	0/74 (0.00%)
Cardiac Arrest ^† 1	0/147 (0.00%)	1/74 (1.35%)
Cardiac failure ^† 1	1/147 (0.68%)	0/74 (0.00%)
Cardiac failure acute ^† 1	1/147 (0.68%)	0/74 (0.00%)
Coronary artery insufficiency ^† 1	0/147 (0.00%)	1/74 (1.35%)
Myocardial infarction ^† 1	0/147 (0.00%)	1/74 (1.35%)
Supraventricular tachycardia ^† 1	0/147 (0.00%)	1/74 (1.35%)
Tachycardia paroxysmal ^† 1	0/147 (0.00%)	1/74 (1.35%)
Ear and labyrinth disorders
Acute vestibular syndrome ^† 1	1/147 (0.68%)	0/74 (0.00%)
Gastrointestinal disorders
Abdominal discomfort ^† 1	1/147 (0.68%)	0/74 (0.00%)
Abdominal pain ^† 1	1/147 (0.68%)	1/74 (1.35%)
Diarrhoea ^† 1	3/147 (2.04%)	3/74 (4.05%)
Haematemesis ^† 1	1/147 (0.68%)	0/74 (0.00%)
Intestinal obstruction ^† 1	1/147 (0.68%)	0/74 (0.00%)
Mallory-Weiss syndrome ^† 1	1/147 (0.68%)	0/74 (0.00%)
Nausea ^† 1	1/147 (0.68%)	0/74 (0.00%)
Pancreatitis chronic ^† 1	1/147 (0.68%)	0/74 (0.00%)
Vomiting ^† 1	1/147 (0.68%)	1/74 (1.35%)
General disorders
Asthenia ^† 1	2/147 (1.36%)	0/74 (0.00%)
Chest pain ^† 1	1/147 (0.68%)	0/74 (0.00%)
Malaise ^† 1	1/147 (0.68%)	0/74 (0.00%)
Multi-organ failure ^† 1	1/147 (0.68%)	1/74 (1.35%)
Pain ^† 1	1/147 (0.68%)	0/74 (0.00%)
Pyrexia ^† 1	4/147 (2.72%)	0/74 (0.00%)
Sudden death ^† 1	1/147 (0.68%)	0/74 (0.00%)
Hepatitis C ^† 1	1/147 (0.68%)	0/74 (0.00%)
Hepatobiliary disorders
Cholecystitis acute ^† 1	1/147 (0.68%)	0/74 (0.00%)
Hepatic failure ^† 1	1/147 (0.68%)	0/74 (0.00%)
Hepatic function abnormal ^† 1	0/147 (0.00%)	1/74 (1.35%)
Hepatitis toxic ^† 1	1/147 (0.68%)	0/74 (0.00%)
Infections and infestations
Bronchitis ^† 1	1/147 (0.68%)	0/74 (0.00%)
Escherichia sepsis ^† 1	0/147 (0.00%)	1/74 (1.35%)
Herpes Zoster ^† 1	2/147 (1.36%)	0/74 (0.00%)
Injection site abscess ^† 1	0/147 (0.00%)	1/74 (1.35%)
Pneumocystis jiroveci pneumonia ^† 1	1/147 (0.68%)	0/74 (0.00%)
Pneumonia ^† 1	9/147 (6.12%)	5/74 (6.76%)
Sepsis ^† 1	0/147 (0.00%)	1/74 (1.35%)
Sinusitis ^† 1	1/147 (0.68%)	0/74 (0.00%)
Skin infection ^† 1	0/147 (0.00%)	1/74 (1.35%)
Urinary tract infection ^† 1	1/147 (0.68%)	0/74 (0.00%)
Injury, poisoning and procedural complications
Humerus fracture ^† 1	1/147 (0.68%)	1/74 (1.35%)
Perianal haematoma ^† 1	1/147 (0.68%)	0/74 (0.00%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	2/147 (1.36%)	0/74 (0.00%)
Dehydration ^† 1	2/147 (1.36%)	0/74 (0.00%)
Hypercalcemia ^† 1	1/147 (0.68%)	1/74 (1.35%)
Hypokalaemia ^† 1	1/147 (0.68%)	0/74 (0.00%)
Tumour lysis syndrome ^† 1	2/147 (1.36%)	1/74 (1.35%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	0/147 (0.00%)	1/74 (1.35%)
Back pain ^† 1	0/147 (0.00%)	1/74 (1.35%)
Pathological fracture ^† 1	1/147 (0.68%)	0/74 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer ^† 1	0/147 (0.00%)	1/74 (1.35%)
Lung neoplasm ^† 1	0/147 (0.00%)	1/74 (1.35%)
Plasmacytoma ^† 1	1/147 (0.68%)	0/74 (0.00%)
Nervous system disorders
Brain oedema ^† 1	0/147 (0.00%)	1/74 (1.35%)
Cerebrovascular disorder ^† 1	0/147 (0.00%)	1/74 (1.35%)
Encephalopathy ^† 1	0/147 (0.00%)	1/74 (1.35%)
Ischaemic stroke ^† 1	0/147 (0.00%)	1/74 (1.35%)
Neuralgia ^† 1	2/147 (1.36%)	0/74 (0.00%)
Paraparesis ^† 1	2/147 (1.36%)	0/74 (0.00%)
Paraplegia ^† 1	1/147 (0.68%)	0/74 (0.00%)
Peripheral neuropathy motor ^† 1	2/147 (1.36%)	1/74 (1.35%)
Peripheral sensorimotor neuropathy ^† 1	1/147 (0.68%)	0/74 (0.00%)
Peripheral sensory neuropathy ^† 1	2/147 (1.36%)	2/74 (2.70%)
Spinal cord compression ^† 1	1/147 (0.68%)	0/74 (0.00%)
Syncope ^† 1	0/147 (0.00%)	1/74 (1.35%)
Toxic encephalopathy ^† 1	1/147 (0.68%)	0/74 (0.00%)
Vascular encephalopathy ^† 1	0/147 (0.00%)	1/74 (1.35%)
Psychiatric disorders
Confusional state ^† 1	0/147 (0.00%)	1/74 (1.35%)
Neurosis ^† 1	1/147 (0.68%)	0/74 (0.00%)
Renal and urinary disorders
Dysuria ^† 1	1/147 (0.68%)	0/74 (0.00%)
Haematuria ^† 1	1/147 (0.68%)	0/74 (0.00%)
Renal failure ^† 1	3/147 (2.04%)	2/74 (2.70%)
Renal failure acute ^† 1	1/147 (0.68%)	0/74 (0.00%)
Renal impairment ^† 1	0/147 (0.00%)	1/74 (1.35%)
Urinary retention ^† 1	1/147 (0.68%)	0/74 (0.00%)
Reproductive system and breast disorders
Vulval ulceration ^† 1	1/147 (0.68%)	0/74 (0.00%)
Respiratory, thoracic and mediastinal disorders
Allergic bronchitis ^† 1	1/147 (0.68%)	0/74 (0.00%)
Bronchospasm ^† 1	1/147 (0.68%)	0/74 (0.00%)
Chronic obstructive pulmonary disease ^† 1	2/147 (1.36%)	1/74 (1.35%)
Cough ^† 1	1/147 (0.68%)	0/74 (0.00%)
Dyspnoea ^† 1	2/147 (1.36%)	1/74 (1.35%)
Lung disorder ^† 1	0/147 (0.00%)	1/74 (1.35%)
Nasal congestion ^† 1	1/147 (0.68%)	0/74 (0.00%)
Pleural effusion ^† 1	0/147 (0.00%)	1/74 (1.35%)
Pleurisy ^† 1	1/147 (0.68%)	1/74 (1.35%)
Vascular disorders
Haematoma ^† 1	1/147 (0.68%)	0/74 (0.00%)
Hypotension ^† 1	0/147 (0.00%)	1/74 (1.35%)
Orthostatic hypotension ^† 1	2/147 (1.36%)	1/74 (1.35%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA (13.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	VELCADE Subcutaneous	VELCADE Intravenous
	Affected / at Risk (%)	Affected / at Risk (%)
Total	112/147 (76.19%)	66/74 (89.19%)
Blood and lymphatic system disorders
Leukopenia ^† 1	29/147 (19.73%)	16/74 (21.62%)
Eye disorders
Chalazion ^† 1	2/147 (1.36%)	4/74 (5.41%)
Gastrointestinal disorders
Abdominal pain upper ^† 1	3/147 (2.04%)	8/74 (10.81%)
Constipation ^† 1	21/147 (14.29%)	11/74 (14.86%)
Dyspepsia ^† 1	4/147 (2.72%)	7/74 (9.46%)
General disorders
Chills ^† 1	6/147 (4.08%)	4/74 (5.41%)
Fatigue ^† 1	17/147 (11.56%)	15/74 (20.27%)
Oedema peripheral ^† 1	9/147 (6.12%)	6/74 (8.11%)
Infections and infestations
Nasopharyngitis ^† 1	4/147 (2.72%)	6/74 (8.11%)
Upper respiratory tract infection ^† 1	7/147 (4.76%)	7/74 (9.46%)
Investigations
Weight decreased ^† 1	22/147 (14.97%)	2/74 (2.70%)
Metabolism and nutrition disorders
Hyperglycaemia ^† 1	7/147 (4.76%)	5/74 (6.76%)
Hyperkalaemia ^† 1	7/147 (4.76%)	1/74 (1.35%)
Musculoskeletal and connective tissue disorders
Bone pain ^† 1	12/147 (8.16%)	2/74 (2.70%)
Muscle spasms ^† 1	4/147 (2.72%)	5/74 (6.76%)
Musculoskeletal pain ^† 1	2/147 (1.36%)	4/74 (5.41%)
Pain in extremity ^† 1	8/147 (5.44%)	8/74 (10.81%)
Nervous system disorders
Dizziness ^† 1	10/147 (6.80%)	2/74 (2.70%)
Headache ^† 1	5/147 (3.40%)	8/74 (10.81%)
Paraesthesia ^† 1	9/147 (6.12%)	6/74 (8.11%)
Psychiatric disorders
Insomnia ^† 1	18/147 (12.24%)	8/74 (10.81%)
Skin and subcutaneous tissue disorders
Pruritis ^† 1	7/147 (4.76%)	2/74 (2.70%)
Rash ^† 1	10/147 (6.80%)	5/74 (6.76%)
Vascular disorders
Hypertension ^† 1	14/147 (9.52%)	3/74 (4.05%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA (13.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

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Name/Title:	Helgi Van de Velde, M.D., Ph.D.
Organization:	Johnson & Johnson Pharmaceutical Research & Development
EMail:	HVDVELDE@ITS.JNJ.COM

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Rekhtman G, Masliak Z, Robak P, Esseltine DL, Feng H, Deraedt W, van de Velde H, Arnulf B. Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study. Haematologica. 2015 May;100(5):e207-10. doi: 10.3324/haematol.2014.118182. Epub 2015 Jan 16. No abstract available.

Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 May;12(5):431-40. doi: 10.1016/S1470-2045(11)70081-X. Epub 2011 Apr 18. Erratum In: Lancet Oncol. 2011 Jun;12(6):522.

Layout table for additonal information

Responsible Party:	Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT00722566
Other Study ID Numbers:	26866138 MMY 3021
First Submitted:	July 23, 2008
First Posted:	July 25, 2008
Results First Submitted:	August 30, 2011
Results First Posted:	October 4, 2011
Last Update Posted:	October 10, 2011

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