A Study to Evaluate Two Different Regimens of VELCADE in Combination With Dexamethasone, Thalidomide and Cyclophosphamide (VDT vs VDTC) in Newly Diagnosed Multiple Myeloma

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00531453
• Collaborator: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Enrollment: 98
• Location: 1
• Arms: 2
• Duration (Months): 19
• Patients Per Site Per Month: 5.2

Study Details

Study Description

Brief Summary

The purpose of this Phase 2 randomized study is to evaluate the efficacy and safety of treatment with a regimen of VELCADE, dexamethasone, and thalidomide (VDT) or VELCADE, dexamethasone, thalidomide, and cyclophosphamide (VDTC) in subjects with newly diagnosed symptomatic multiple myeloma who have received no prior treatment and are candidates to receive high-dose therapy and autologous bone marrow/stem cell transplantation.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: bortezomib, dexamethasone, and thalidomide; Drug: bortezomib, dexamethasone, thalidomide, and cyclophosphamide	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 98 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized Study of VELCADE® (Bortezomib), Dexamethasone, and Thalidomide Versus VELCADE® (Bortezomib), Dexamethasone, Thalidomide, and Cyclophosphamide in Subjects With Previously Untreated Multiple Myeloma Who Are Candidates for Autologous Transplantation
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 bortezomib, dexamethasone, and thalidomide	Drug: bortezomib, dexamethasone, and thalidomide; VELCADE (bortezomib) twice weekly for 4 cycles (4 doses per cycle), prior to high-dose chemotherapy (HDT) and stem cell transplantation(SCT). Subjects will receive VELCADE 1.3 mg/m2 as an intravenous (i.v.) bolus injection on Days 1,4,8, and 11, followed by a 10 day rest period (Days 12 to 21) Dexamethasone 40 mg/day will be given by mouth (p.o.) on Days 1-4 and Days 9-12 in each of 4 cycles. Thalidomide will be given by mouth (p.o.)every day, starting on Day 1 of Cycle 1 (e.g. the same day of the first dose of VELCADE) and continuing until Day 21 of Cycle 4 at a dose of 100 mg/day (bedtime).
Experimental: 2 bortezomib, dexamethasone, thalidomide, and cyclophosphamide	Drug: bortezomib, dexamethasone, thalidomide, and cyclophosphamide; VELCADE (bortezomib) twice weekly for 4 cycles (4 doses per cycle), prior to high-dose chemotherapy(HDT)and stem cell transplantation(SCT). Subjects will receive VELCADE 1.3 mg/m2 as an intravenous (i.v.) bolus injection on Days 1,4,8, and 11, followed by a 10 day rest period (Days 12 to 21). Dexamethasone 40 mg/day will be given by mouth (p.o.) on Days 1-4 and Days 9-12 in each of 4 cycles. Thalidomide will be given by mouth (p.o.) every day, starting on Day 1 of Cycle 1 (e.g., the same day of the first dose of VELCADE) and continuing until Day 21 of Cycle 4 at a dose of 100 mg/day (bedtime). Cyclophosphamide will be given as an intravenous (i.v.) dose of 400 mg/m2 on Day 1 and Day 8 of each 3-week cycle, for a total of 4 cycles.

Outcome Measures

Primary Outcome Measures

1. Percent of Particpants Achieving Overall Combined Complete Response (CR) Following Induction [all data included in clinical database as of 10 April 2009]

   Percent of Particpants Achieving Overall combined complete response (CR w/normalized serum κ:λ ratio + CR + near complete response (nCR)) following induction therapy. CR criteria: negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. κ:λ ratio: normal free light chain (FLC) ratio nCR criteria: positive immunofixation analysis of serum or urine as the only evidence of disease; disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow.

Secondary Outcome Measures

1. Percent of Participants Achieving Overall Combined Complete Response (CR) Following High-dose Chemotherapy (HDT)/Stem Cell Transplantation (SCT) [all data included in clinical database as of 10 April 2009]

   Percent of Participants Achieving Overall Combined Complete Response (CR) (CR w/normalized serum κ:λ ratio + CR + Near Complete Response (nCR)) following stem cell transplantation. CR criteria: negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. κ:λ ratio: normal free light chain (FLC) ratio nCR criteria: positive immunofixation analysis of serum or urine as the only evidence of disease; disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female between ≥18 and ≤70 years

• Patient is a candidate for HDT combined with an autologous SCT

• Karnofsky Performance Status score of ≥60%

• Multiple myeloma diagnosed according to the following standard criteria AND requiring systemic therapy:

• Presence of M-component in serum and/or urine, plus clonal plasma cells in the bone marrow and/or a documented clonal plasmacytoma

• PLUS 1 or more of the following:

1. Calcium elevation (>11.5 mg/dL or >2.65 mmol/L)

2. Renal insufficiency (creatinine >2 mg/dL or >177 umol/L)

3. Anemia (hemoglobin <10 g/dL [<12.5 mmol/L] or at least 2 mg/dL [1.25 mmol/L] below normal)

4. Bone disease (lytic lesions or osteopenia)

• AND fulfill criteria for measurable disease, as defined by at least 1 of the following 3 measurements:

1. Serum M-protein ≥1 g/dL (≥10 g/L)

2. Urine M-protein ≥200 mg/24 h

3. Serum free light chain (FLC) assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal

• Women of childbearing potential must agree to use 2 methods of contraception.

• Males must agree to use barrier contraception.

• Subjects (or their legally acceptable representatives) must have signed an informed consent document.

• To participate in the optional pharmacogenomic component of this study, subjects (or their legally acceptable representative) must have signed the informed consent form. Refusal to consent for this component does not exclude a subject from participation in the clinical study.

Exclusion Criteria:

• Diagnosis of smoldering OR non-secretory multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS).

• Diagnosis of Waldenström's disease or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.

• Prior or current systemic therapy for multiple myeloma including steroids.

• Radiation therapy and/or plasmapheresis within 15 days before randomization.

• History of allergic reaction attributable to compounds being given (VELCADE, thalidomide, dexamethasone, and/or cyclophosphamide) or compounds containing boron or mannitol.

• Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

• Uncontrolled or severe cardiovascular disease

• Concurrent medical condition or disease (e.g., active systemic infection, uncontrolled diabetes) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study.

• Use of any investigational drugs within 30 days before randomization

• Pregnant or lactating women: A serum β-hCG pregnancy test must be performed at the Screening visit for female subjects of childbearing potential.

• Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wilhelminenspital-1	Vienna		Austria	A-1160

Sponsors and Collaborators

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

Investigators

• Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT00531453
• Other Study ID Numbers: 26866138-MMY-2043
• First Posted: Sep 18, 2007
• Last Update Posted: Jan 26, 2012
• Last Verified: Jan 1, 2012

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Thalidomide; Dexamethasone; Dexamethasone acetate; Cyclophosphamide; Bortezomib; BB 1101

Study Results

Participant Flow

Recruitment Details	98 patients were enrolled between October 2007 and September 2008
Pre-assignment Detail	All enrolled patients received at least one dose of study drug.

Arm/Group Title	Three Drug Regimen (VDT)	Four Drug Regimen (VDTC)
Arm/Group Description	bortezomib, dexamethasone, and thalidomide	bortezomib, dexamethasone, thalidomide, and cyclophosphamide
Period Title: Overall Study
STARTED	49	49
COMPLETED	49	49
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Three Drug Regimen (VDT)	Four Drug Regimen (VDTC)	Total
Arm/Group Description	bortezomib, dexamethasone, and thalidomide	bortezomib, dexamethasone, thalidomide, and cyclophosphamide	Total of all reporting groups
Overall Participants	49	49	98
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	46 93.9%	44 89.8%	90 91.8%
>=65 years	3 6.1%	5 10.2%	8 8.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.1 (7.04)	55.8 (8.27)	55.4 (7.65)
Sex: Female, Male (Count of Participants)
Female	26 53.1%	25 51%	51 52%
Male	23 46.9%	24 49%	47 48%

Outcome Measures

1. Primary Outcome

Title	Percent of Particpants Achieving Overall Combined Complete Response (CR) Following Induction
Description	Percent of Particpants Achieving Overall combined complete response (CR w/normalized serum κ:λ ratio + CR + near complete response (nCR)) following induction therapy. CR criteria: negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. κ:λ ratio: normal free light chain (FLC) ratio nCR criteria: positive immunofixation analysis of serum or urine as the only evidence of disease; disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow.
Time Frame	all data included in clinical database as of 10 April 2009

Outcome Measure Data

Analysis Population Description

The response-evaluable population is defined as all subjects who have measurable disease at baseline, receive at least 1 dose of any study drug and have at least 1 post-baseline response assessment. The response-evaluable population comprises 49 subjects in the VDT treatment group and 48 subjects in the VDTC group.

Arm/Group Title	Three Drug Regimen (VDT)	Four Drug Regimen (VDTC)
Arm/Group Description	bortezomib, dexamethasone, and thalidomide	bortezomib, dexamethasone, thalidomide, and cyclophosphamide
Measure Participants	49	48
Number [percentage of participants]	51 104.1%	44 89.8%

2. Secondary Outcome

Title	Percent of Participants Achieving Overall Combined Complete Response (CR) Following High-dose Chemotherapy (HDT)/Stem Cell Transplantation (SCT)
Description	Percent of Participants Achieving Overall Combined Complete Response (CR) (CR w/normalized serum κ:λ ratio + CR + Near Complete Response (nCR)) following stem cell transplantation. CR criteria: negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. κ:λ ratio: normal free light chain (FLC) ratio nCR criteria: positive immunofixation analysis of serum or urine as the only evidence of disease; disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow.
Time Frame	all data included in clinical database as of 10 April 2009

Outcome Measure Data

Analysis Population Description

The response-evaluable population is defined as all subjects who have measurable disease at baseline, receive at least 1 dose of any study drug and have at least 1 post-transplantation response assessment. The response-evaluable population comprises 38 subjects in the VDT treatment group and 27 subjects in the VDTC group.

Arm/Group Title	Three Drug Regimen (VDT)	Four Drug Regimen (VDTC)
Arm/Group Description	bortezomib, dexamethasone, and thalidomide	bortezomib, dexamethasone, thalidomide, and cyclophosphamide
Measure Participants	38	27
Number [percentage of participants]	76 155.1%	78 159.2%

Adverse Events

Time Frame	From first dose to 30 days post last dose
Adverse Event Reporting Description	Treatment emergent
Arm/Group Title	Three Drug Regimen (VDT)		Four Drug Regimen (VDTC)
Arm/Group Description	bortezomib, dexamethasone, and thalidomide		bortezomib, dexamethasone, thalidomide, and cyclophosphamide
All Cause Mortality
	Three Drug Regimen (VDT)		Four Drug Regimen (VDTC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Three Drug Regimen (VDT)		Four Drug Regimen (VDTC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/49 (22.4%)		20/49 (40.8%)
Blood and lymphatic system disorders
Blood and Lymphatic System Disorders	1/49 (2%)		2/49 (4.1%)
Cardiac disorders
Cardiac Disorders	1/49 (2%)		2/49 (4.1%)
Gastrointestinal disorders
Gastrointestinal Disorders	4/49 (8.2%)		4/49 (8.2%)
General disorders
General Disorders and administration site Conditions	4/49 (8.2%)		4/49 (8.2%)
Infections and infestations
Infections and Infestations	3/49 (6.1%)		7/49 (14.3%)
Injury, poisoning and procedural complications
Injury, Poisoning and Procedural Complications	0/49 (0%)		2/49 (4.1%)
Metabolism and nutrition disorders
Metabolism and Nutritional Disorders	1/49 (2%)		1/49 (2%)
Musculoskeletal and connective tissue disorders
Musculoskeletal and Connective Tissue Disorders	1/49 (2%)		7/49 (14.3%)
Nervous system disorders
Nervous System Disorders	3/49 (6.1%)		2/49 (4.1%)
Psychiatric disorders
Psychiatric Disorders	0/49 (0%)		1/49 (2%)
Renal and urinary disorders
Renal and Urinary Disorders	1/49 (2%)		0/49 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory, Thoracic and mediastinal Disorders	3/49 (6.1%)		4/49 (8.2%)
Skin and subcutaneous tissue disorders
Skin and Subcutaneous Tissue Disorders	0/49 (0%)		1/49 (2%)
Vascular disorders
Vascular Disorders	0/49 (0%)		1/49 (2%)
Other (Not Including Serious) Adverse Events
	Three Drug Regimen (VDT)		Four Drug Regimen (VDTC)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/49 (98%)		47/49 (95.9%)
Blood and lymphatic system disorders
Blood and Lymphatic System Disorders	15/49 (30.6%)		22/49 (44.9%)
Cardiac disorders
Cardiac Disorders	1/49 (2%)		3/49 (6.1%)
Ear and labyrinth disorders
Ear and labyrinth Disorders	3/49 (6.1%)		3/49 (6.1%)
Endocrine disorders
Endocrine Disorders	1/49 (2%)		0/49 (0%)
Eye disorders
Eye Disorders	6/49 (12.2%)		6/49 (12.2%)
Gastrointestinal disorders
Gastrointestinal Disorders	30/49 (61.2%)		32/49 (65.3%)
General disorders
General Disorders and Administration Site Conditions	28/49 (57.1%)		28/49 (57.1%)
Hepatobiliary disorders
Hepatobiliary Disorders	7/49 (14.3%)		3/49 (6.1%)
Immune system disorders
Immune System Disorders	0/49 (0%)		1/49 (2%)
Infections and infestations
Infections and Infestations	15/49 (30.6%)		11/49 (22.4%)
Injury, poisoning and procedural complications
Injury, Poisoning and Procedural Complications	1/49 (2%)		3/49 (6.1%)
Investigations
Investigations	2/49 (4.1%)		5/49 (10.2%)
Metabolism and nutrition disorders
Metabolism and Nutrition Disorders	16/49 (32.7%)		15/49 (30.6%)
Musculoskeletal and connective tissue disorders
Musculoskeletal and Connective Tissue Disorders	17/49 (34.7%)		13/49 (26.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms Benign, Malignant and Unspecified	0/49 (0%)		1/49 (2%)
Nervous system disorders
Nervous System Disorders	31/49 (63.3%)		27/49 (55.1%)
Psychiatric disorders
Psychiatric Disorders	9/49 (18.4%)		8/49 (16.3%)
Renal and urinary disorders
Renal and Urinary Disorders	2/49 (4.1%)		2/49 (4.1%)
Reproductive system and breast disorders
Reproductive System and Brest Disorders	0/49 (0%)		1/49 (2%)
Respiratory, thoracic and mediastinal disorders
Respiratory, Thoracic and Mediastinal Disorders	9/49 (18.4%)		9/49 (18.4%)
Skin and subcutaneous tissue disorders
Skin and Subcutaneous Tissue Disorders	18/49 (36.7%)		12/49 (24.5%)
Vascular disorders
Vascular Disorders	8/49 (16.3%)		13/49 (26.5%)

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.