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

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00722566
• Collaborator: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Enrollment: 222
• Locations: 3
• Arms: 2
• Duration (Months): 26
• Patients Per Site: 74
• Patients Per Site Per Month: 2.8

Study Details

Study Description

Brief Summary

Randomized, open-label, international, multi-center, Phase 3 study in which patients are randomized to receive VELCADE administered by subcutaneous injection or intravenous infusion.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: VELCADE Administered by subcutaneous injection; Drug: VELCADE Administered by intravenous infusion	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 222 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Randomized Study of Subcutaneous and Intravenous VELCADE in Subjects With Previously Treated Multiple Myeloma
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Sep 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 VELCADE administered by subcutaneous injection	Drug: VELCADE Administered by subcutaneous injection; Patients will receive a 1.3mg/meters(squared)/dose of VELCADE on Days 1,4,8, and 11 of a 3-week cycle
Active Comparator: 2 VELCADE administered by intravenous infusion	Drug: VELCADE Administered by intravenous infusion; Patients will receive a 1.3mg/meters(squared) dose of VELCADE on Days 1,4,8, and 11 of a 3-week cycle.

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Overall Response (Complete Response + Partial Response) [Over 4 cycles (prior to the addition of dexamethasone)]

   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

Secondary Outcome Measures

1. Number of Patients With Complete Response [Over 4 cycles (prior to the addition of dexamethasone)]

   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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Male or female subjects 18 years or older

2. Diagnosis of multiple myeloma

3. Measurable, secretory multiple myeloma defined as serum monoclonal IgG of ≥10 g/L, serum monoclonal IgA or IgE ≥5 g/L, or serum monoclonal IgD ≥0.5g/L; or urine M-protein of ≥200 mg/24 hr

4. Relapse or progression of myeloma following prior systemic antineoplastic therapy.

Exclusion Criteria:

1. Previous treatment with VELCADE

2. More than 3 previous lines of therapy (separate lines of therapy are defined as single or combination therapies that are either separated by disease progression or by a greater than 6 month treatment-free interval)

3. Peripheral neuropathy or neuropathic pain of NCI CTCAE Grade ≥2

4. Any of the following within 3 weeks prior to randomization:

antineoplastic or experimental therapy, corticosteroid use above 10mg a day (prednisone or equivalent), or plasmapheresis

1. Any of the following within 2 weeks prior to randomization:

radiation therapy, major surgery (kyphoplasty is not considered major surgery)

1. Prior malignancy other than multiple myeloma diagnosed or treated within the last 2 years, with the exception of completely resected carcinoma in situ or basal/squamous carcinoma of the skin

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UZ Brussel Department Medical Oncology Laarbeeklaan 101	Brussel		Belgium	1090
2	Hôtel DIEU, Service D'Hématologie Place Alexis RICORDEAU	NANTES Cedex 01		France	44093
3	Universitätsklinikum Münster Onkologische Ambulanz West Albert-Schweitzer-Str. 33	Münster		Germany	48129

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.
• Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Investigators

• Study Director: Medical Monitor, Ortho Biotech Oncology Research & Development - Unit of Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT00722566
• Other Study ID Numbers: 26866138 MMY 3021
• First Posted: Jul 25, 2008
• Last Update Posted: Oct 10, 2011
• Last Verified: Oct 1, 2011

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Bortezomib

Study Results

Participant Flow

Arm/Group Title	VELCADE Subcutaneous	VELCADE Intravenous
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	74
COMPLETED	81	39
NOT COMPLETED	67	35

Baseline Characteristics

Arm/Group Title	VELCADE Subcutaneous	VELCADE Intravenous	Total
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 Participants	148	74	222
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	74 50%	37 50%	111 50%
>=65 years	74 50%	37 50%	111 50%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.3 (8.96)	64.0 (12.11)	64.2 (10.09)
Sex: Female, Male (Count of Participants)
Female	74 50%	27 36.5%	101 45.5%
Male	74 50%	47 63.5%	121 54.5%
Region of Enrollment (participants) [Number]
France	22 14.9%	14 18.9%	36 16.2%
Belgium	7 4.7%	5 6.8%	12 5.4%
Germany	2 1.4%	4 5.4%	6 2.7%
Netherlands	6 4.1%	4 5.4%	10 4.5%
United Kingdom	6 4.1%	3 4.1%	9 4.1%
Ukraine	51 34.5%	17 23%	68 30.6%
Russian Federation	26 17.6%	9 12.2%	35 15.8%
Poland	20 13.5%	7 9.5%	27 12.2%
Argentina	5 3.4%	8 10.8%	13 5.9%
India	3 2%	3 4.1%	6 2.7%

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 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 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.
Measure Participants	145	73
Number [Participants]	61 41.2%	31 41.9%

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
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Patients With Complete Response
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

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 Subcutaneous	VELCADE Intravenous
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.
Measure Participants	145	73
Number [Participants]	9 6.1%	6 8.1%

Adverse Events

Arm/Group Title	VELCADE Subcutaneous		VELCADE Intravenous
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	VELCADE Subcutaneous		VELCADE Intravenous
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/147 (36.1%)		26/74 (35.1%)
Blood and lymphatic system disorders
Anemia	0/147 (0%)		1/74 (1.4%)
Neutropenia	1/147 (0.7%)		1/74 (1.4%)
Splenomegaly	1/147 (0.7%)		0/74 (0%)
Thrombocytopenia	1/147 (0.7%)		1/74 (1.4%)
Cardiac disorders
Angina Pectoris	1/147 (0.7%)		0/74 (0%)
Arrhythmia	1/147 (0.7%)		0/74 (0%)
Arteriosclerosis coronary artery	1/147 (0.7%)		0/74 (0%)
Atrial Fibrillation	2/147 (1.4%)		0/74 (0%)
Bradyarrhythmia	1/147 (0.7%)		0/74 (0%)
Cardiac Arrest	0/147 (0%)		1/74 (1.4%)
Cardiac failure	1/147 (0.7%)		0/74 (0%)
Cardiac failure acute	1/147 (0.7%)		0/74 (0%)
Coronary artery insufficiency	0/147 (0%)		1/74 (1.4%)
Myocardial infarction	0/147 (0%)		1/74 (1.4%)
Supraventricular tachycardia	0/147 (0%)		1/74 (1.4%)
Tachycardia paroxysmal	0/147 (0%)		1/74 (1.4%)
Ear and labyrinth disorders
Acute vestibular syndrome	1/147 (0.7%)		0/74 (0%)
Gastrointestinal disorders
Abdominal discomfort	1/147 (0.7%)		0/74 (0%)
Abdominal pain	1/147 (0.7%)		1/74 (1.4%)
Diarrhoea	3/147 (2%)		3/74 (4.1%)
Haematemesis	1/147 (0.7%)		0/74 (0%)
Intestinal obstruction	1/147 (0.7%)		0/74 (0%)
Mallory-Weiss syndrome	1/147 (0.7%)		0/74 (0%)
Nausea	1/147 (0.7%)		0/74 (0%)
Pancreatitis chronic	1/147 (0.7%)		0/74 (0%)
Vomiting	1/147 (0.7%)		1/74 (1.4%)
General disorders
Asthenia	2/147 (1.4%)		0/74 (0%)
Chest pain	1/147 (0.7%)		0/74 (0%)
Malaise	1/147 (0.7%)		0/74 (0%)
Multi-organ failure	1/147 (0.7%)		1/74 (1.4%)
Pain	1/147 (0.7%)		0/74 (0%)
Pyrexia	4/147 (2.7%)		0/74 (0%)
Sudden death	1/147 (0.7%)		0/74 (0%)
Hepatitis C	1/147 (0.7%)		0/74 (0%)
Hepatobiliary disorders
Cholecystitis acute	1/147 (0.7%)		0/74 (0%)
Hepatic failure	1/147 (0.7%)		0/74 (0%)
Hepatic function abnormal	0/147 (0%)		1/74 (1.4%)
Hepatitis toxic	1/147 (0.7%)		0/74 (0%)
Infections and infestations
Bronchitis	1/147 (0.7%)		0/74 (0%)
Escherichia sepsis	0/147 (0%)		1/74 (1.4%)
Herpes Zoster	2/147 (1.4%)		0/74 (0%)
Injection site abscess	0/147 (0%)		1/74 (1.4%)
Pneumocystis jiroveci pneumonia	1/147 (0.7%)		0/74 (0%)
Pneumonia	9/147 (6.1%)		5/74 (6.8%)
Sepsis	0/147 (0%)		1/74 (1.4%)
Sinusitis	1/147 (0.7%)		0/74 (0%)
Skin infection	0/147 (0%)		1/74 (1.4%)
Urinary tract infection	1/147 (0.7%)		0/74 (0%)
Injury, poisoning and procedural complications
Humerus fracture	1/147 (0.7%)		1/74 (1.4%)
Perianal haematoma	1/147 (0.7%)		0/74 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/147 (1.4%)		0/74 (0%)
Dehydration	2/147 (1.4%)		0/74 (0%)
Hypercalcemia	1/147 (0.7%)		1/74 (1.4%)
Hypokalaemia	1/147 (0.7%)		0/74 (0%)
Tumour lysis syndrome	2/147 (1.4%)		1/74 (1.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/147 (0%)		1/74 (1.4%)
Back pain	0/147 (0%)		1/74 (1.4%)
Pathological fracture	1/147 (0.7%)		0/74 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	0/147 (0%)		1/74 (1.4%)
Lung neoplasm	0/147 (0%)		1/74 (1.4%)
Plasmacytoma	1/147 (0.7%)		0/74 (0%)
Nervous system disorders
Brain oedema	0/147 (0%)		1/74 (1.4%)
Cerebrovascular disorder	0/147 (0%)		1/74 (1.4%)
Encephalopathy	0/147 (0%)		1/74 (1.4%)
Ischaemic stroke	0/147 (0%)		1/74 (1.4%)
Neuralgia	2/147 (1.4%)		0/74 (0%)
Paraparesis	2/147 (1.4%)		0/74 (0%)
Paraplegia	1/147 (0.7%)		0/74 (0%)
Peripheral neuropathy motor	2/147 (1.4%)		1/74 (1.4%)
Peripheral sensorimotor neuropathy	1/147 (0.7%)		0/74 (0%)
Peripheral sensory neuropathy	2/147 (1.4%)		2/74 (2.7%)
Spinal cord compression	1/147 (0.7%)		0/74 (0%)
Syncope	0/147 (0%)		1/74 (1.4%)
Toxic encephalopathy	1/147 (0.7%)		0/74 (0%)
Vascular encephalopathy	0/147 (0%)		1/74 (1.4%)
Psychiatric disorders
Confusional state	0/147 (0%)		1/74 (1.4%)
Neurosis	1/147 (0.7%)		0/74 (0%)
Renal and urinary disorders
Dysuria	1/147 (0.7%)		0/74 (0%)
Haematuria	1/147 (0.7%)		0/74 (0%)
Renal failure	3/147 (2%)		2/74 (2.7%)
Renal failure acute	1/147 (0.7%)		0/74 (0%)
Renal impairment	0/147 (0%)		1/74 (1.4%)
Urinary retention	1/147 (0.7%)		0/74 (0%)
Reproductive system and breast disorders
Vulval ulceration	1/147 (0.7%)		0/74 (0%)
Respiratory, thoracic and mediastinal disorders
Allergic bronchitis	1/147 (0.7%)		0/74 (0%)
Bronchospasm	1/147 (0.7%)		0/74 (0%)
Chronic obstructive pulmonary disease	2/147 (1.4%)		1/74 (1.4%)
Cough	1/147 (0.7%)		0/74 (0%)
Dyspnoea	2/147 (1.4%)		1/74 (1.4%)
Lung disorder	0/147 (0%)		1/74 (1.4%)
Nasal congestion	1/147 (0.7%)		0/74 (0%)
Pleural effusion	0/147 (0%)		1/74 (1.4%)
Pleurisy	1/147 (0.7%)		1/74 (1.4%)
Vascular disorders
Haematoma	1/147 (0.7%)		0/74 (0%)
Hypotension	0/147 (0%)		1/74 (1.4%)
Orthostatic hypotension	2/147 (1.4%)		1/74 (1.4%)
Other (Not Including Serious) Adverse Events
	VELCADE Subcutaneous		VELCADE Intravenous
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/147 (76.2%)		66/74 (89.2%)
Blood and lymphatic system disorders
Leukopenia	29/147 (19.7%)		16/74 (21.6%)
Eye disorders
Chalazion	2/147 (1.4%)		4/74 (5.4%)
Gastrointestinal disorders
Abdominal pain upper	3/147 (2%)		8/74 (10.8%)
Constipation	21/147 (14.3%)		11/74 (14.9%)
Dyspepsia	4/147 (2.7%)		7/74 (9.5%)
General disorders
Chills	6/147 (4.1%)		4/74 (5.4%)
Fatigue	17/147 (11.6%)		15/74 (20.3%)
Oedema peripheral	9/147 (6.1%)		6/74 (8.1%)
Infections and infestations
Nasopharyngitis	4/147 (2.7%)		6/74 (8.1%)
Upper respiratory tract infection	7/147 (4.8%)		7/74 (9.5%)
Investigations
Weight decreased	22/147 (15%)		2/74 (2.7%)
Metabolism and nutrition disorders
Hyperglycaemia	7/147 (4.8%)		5/74 (6.8%)
Hyperkalaemia	7/147 (4.8%)		1/74 (1.4%)
Musculoskeletal and connective tissue disorders
Bone pain	12/147 (8.2%)		2/74 (2.7%)
Muscle spasms	4/147 (2.7%)		5/74 (6.8%)
Musculoskeletal pain	2/147 (1.4%)		4/74 (5.4%)
Pain in extremity	8/147 (5.4%)		8/74 (10.8%)
Nervous system disorders
Dizziness	10/147 (6.8%)		2/74 (2.7%)
Headache	5/147 (3.4%)		8/74 (10.8%)
Paraesthesia	9/147 (6.1%)		6/74 (8.1%)
Psychiatric disorders
Insomnia	18/147 (12.2%)		8/74 (10.8%)
Skin and subcutaneous tissue disorders
Pruritis	7/147 (4.8%)		2/74 (2.7%)
Rash	10/147 (6.8%)		5/74 (6.8%)
Vascular disorders
Hypertension	14/147 (9.5%)		3/74 (4.1%)

Limitations/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.