MMVAR - Velcade: Study of Velcade for the Treatment of Myeloma Patients After Autologous Transplantation

• Sponsor: European Society for Blood and Marrow Transplantation (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00256776
• Collaborator: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry), Celgene Corporation (Industry)
• Enrollment: 269
• Locations: 81
• Arms: 2
• Duration (Months): 125
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is an international study in adult patients diagnosed with multiple myeloma who have already received at least one autologous stem cell transplantation and who have responded but later progressed, or relapsed, at least one year after transplantation.

Eligible patients will be randomly assigned to one of two treatments: either Velcade plus Thalidomide plus Dexamethasone or Thalidomide plus Dexamethasone.

Thalidomide and Velcade are two new agents that have recently become available for the treatment of multiple myeloma, especially in relapsed patients. This study therefore aims to test the hypothesis that the combination treatment with Velcade plus Thalidomide plus Dexamethasone will result in a longer time to progression (measure of time after the disease is treated until it starts to get worse) than Thalidomide plus Dexamethasone alone.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Velcade (Bortezomib); Drug: Thalidomide; Drug: Dexamethasone	Phase 3

Detailed Description

Primary Objectives:

• Test the hypothesis that treatment with Velcade plus Thalidomide plus Dexamethasone in combination, will result in a longer time to progression (TTP) than Thalidomide plus Dexamethasone in subjects with relapsed or progressive myeloma after autologous transplantation.

Secondary Objectives:

• Compare the treatment groups for: overall survival; response rate (complete & partial & minimal) using standard criteria and treatment related complications.

Study design and methodology:

This is a prospective, randomized, parallel-group, open-label phase III, on an intention to treat, multicenter study. The main endpoint is time-to-failure (TTP=time to progression). The power is based on an initial assumption of a median TTP of 1.5 years in the experimental (Velcade) group and 1 year in the control group. The design of the study is group sequential. There will be 4 interim analyses and one final analysis. The study is designed to have a priori 90% power to detect the clinically relevant difference at completion of the study at 0.025 level. Patients with multiple myeloma whose disease has either progressed or relapsed at least one year after one or two autologous transplantations will be enrolled. Prior to random assignment, subjects will be stratified on center and number of autologous transplants.Subjects will be randomly assigned to treatment in a 1: 1 allocation within each stratum to Velcade plus Thalidomide plus Dexamethasone (VTD) or Thalidomide plus Dexamethasone. Velcade 1.3 mg/m2 will be given as an i.v. bolus on Days 1, 4, 8 and 11 followed by a 10-day rest period (Days 12 to 21) for 8 cycles (6 months) and then on Days 1, 8, 15, and 22 followed by a 20-day rest period (Days 23 to 42) for 4 cycles (6 months). In both arms, Thalidomide will be given at 200 mg/day per os for one year and Dexamethasone 40 mg/day per os four days every three weeks for one year.Treatment will continue until disease progression, or the occurrence of unacceptable treatment-related toxicity, or up to a total of 12 cycles of Velcade except for those subjects who have a continuing decrease in the levels of paraprotein after 12 cycles. These subjects may continue for as long as treatment is tolerated, and they continue to respond. If a subject has a CR, then treatment should continue at least 2 cycles after the objective response is confirmed. For subjects with a PR or stable disease, treatment may continue after a maximum objective response is confirmed unless the subject experiences unacceptable treatment-related toxicity or the subject has completed 12 cycles of treatment. Disease assessment will occur at the start of each cycle. If a subject discontinues treatment without disease progression, disease assessment will be performed every 3 weeks for 48-weeks from the start of the first dose of study entry drug. Subjects who have not progressed at the end of 48-week follow up period will be assessed every 6 weeks until disease progression is documented

Study Design

• Study Type: Interventional
• Actual Enrollment: 269 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Controlled Study of Velcade (Bortezomib) Plus Thalidomide Plus Dexamethasone Compared to Thalidomide Plus Dexamethasone for the Treatment of Myeloma Patients Progressing or Relapsing After Autologous Transplantation
• Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Thal + Dex + Velcade	Drug: Velcade (Bortezomib); Drug: Thalidomide; Drug: Dexamethasone
Active Comparator: Thal + Dex Standard treatment	Drug: Thalidomide; Drug: Dexamethasone

Outcome Measures

Primary Outcome Measures

1. Median Time to Progression (TTP) [3 year]

Secondary Outcome Measures

1. Progression Free Survival [3 year]

2. Overall Survival (Interval Between Date of Randomization and Death From Any Cause [1 year]

3. Response Rate (Proportion of Subjects Who Achieve Complete, Partial, or Minimal Response) [1 year]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female ≥18 years-of-age

• Multiple myeloma with evaluable disease

• Relapsing or having a progressive disease

• Karnofsky performance status > 50 %

• Life expectancy of at least 3 months

• Female of child-bearing potential must have a method of birth control and a negative serum or urine beta--human chorionic gonadotropin (β-HCG) pregnancy test at screening and all through the study

• Male must use contraception

• Voluntary written informed consent

Exclusion Criteria:

• Non-secretory multiple myeloma

• Platelet count < 40,000 X 10^9/L

• Absolute neutrophil count <1.0 X 10^9/L

• Creatinine clearance <30 mL/minute

• Peripheral neuropathy >= Grade 2

• Seropositive for HIV, or active hepatitis A, B or C infection

• Pregnant or breastfeeding female

• Patient has hypersensitivity to bortezomib, boron or mannitol

• Other investigational drugs

• Serious medical or psychiatric illness

• Previous or concurrent malignancies at other sites

• Poorly controlled hypertension, uncontrolled or severe cardiovascular disease or uncontrolled diabetes mellitus

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Karl-Franzens	Graz		Austria
2	Universitatsklinik	Innsbruck		Austria
3	Medizinische Universitaet Wien	Vienna		Austria
4	Wilhelminenspital	Vienna		Austria
5	St Joseph	Arlon		Belgium
6	RHMS	Baudour		Belgium
7	AZ St Jan	Brugge		Belgium
8	Bordet	Brussels		Belgium
9	Erasme CHU	Brussels		Belgium
10	Saint Luc	Brussels		Belgium
11	University Hospital	Brussels		Belgium
12	Saint Joseph	Gilly		Belgium
13	CH Jolimont	Haine-Saint-Paul		Belgium
14	Clinique Saint-Pierre	Ottignies		Belgium
15	UCL Mont-Godinne	Yvoir		Belgium
16	University Hospital	Brno		Czechia
17	Faculty Hospital	Olomouc		Czechia
18	CHU Amiens	Amiens		France
19	CHU Angers	Angers		France
20	Centre Hospitalier d'Antibes	Antibes		France
21	CHU Jean Minjoz	Besancon		France
22	Avicenne	Bobigny		France
23	Polyclinique Bordeaux Nord	Bordeaux		France
24	Morvan CHU	Brest		France
25	Hotel Dieu	Clermont-Ferrand		France
26	ARC CHU Dijon	Dijon		France
27	Hospitalier de Dunkerque	Dunkerque		France
28	Hopital Michallon	Grenoble		France
29		La Roche sur Yon		France
30	Centre Hospitalier du Havre	Le Havre		France
31	CHRU de Lille	Lille		France
32	Edouard Herriot	Lyon		France
33	Pierre Benite	Lyon		France
34		Metz		France
35	Centre Hospitalier de Mulhouse	Mulhouse		France
36	CHU Nancy	Nancy		France
37	Hotel Dieu	Nantes		France
38	Archet	Nice		France
39	Hopital Cochin	Paris		France
40	Hotel Dieu	Paris		France
41	Saint Antoine	Paris		France
42	Hopital Jean Bernard	Poitiers		France
43	Robert Debre	Reims		France
44	CHU Hopital Sud	Rennes		France
45	Henri Becquerel	Rouen		France
46	CHRU Tours	Tours		France
47	Klinikum Bremen	Bremen		Germany
48	University of Cologne	Cologne		Germany
49	University Hospital	Dresden		Germany
50	University Hospital	Hamburg		Germany
51	Medizinische Hochschule	Hannover		Germany
52	Uniklinik Leipzig	Leipzig		Germany
53	Universitatsklinikum Schleswig-Hostein	Lubeck		Germany
54	DKD Wiesbaden	Wiesbaden		Germany
55	Medizinische und Poliklinik II	Wurzburg		Germany
56	St Laszlo Hospital	Budapest		Hungary
57	University of Debrecen	Debrecen		Hungary
58	Rambam MC	Haifa		Israel
59	Sheba MC	Tel Hashomer		Israel
60	Ospedale SS. Antonio e Biagio e Cesare Arrigo	Alessandria		Italy
61	Ospedale Riuniti	Bergamo		Italy
62	AO Spedali Civili di Brescia	Brescia		Italy
63	Ospedale Maggiore	Catania		Italy
64	Ospedale Maggiore	Milan		Italy
65	Federico II	Naples		Italy
66	V. Cervello	Palermo		Italy
67	Azienda Ospedale BMM	Reggio di Calabria		Italy
68	A.O.S. Andrea	Rome		Italy
69	Kantonsspital Aarau	Aarau		Switzerland
70	Kantonsspital Baden	Baden		Switzerland
71	Kantonsspital	Basel		Switzerland
72	IOSI, Ospedale Civico	Bellinzona		Switzerland
73	Inselspital	Bern		Switzerland
74	Hopital Cantonal Universitaire	Geneva		Switzerland
75	CHUV	Lausanne		Switzerland
76	LA Onkologie/Medizin	Thun		Switzerland
77	Stadtdpital Triemli	Zurich		Switzerland
78	UniversitatsSpital	Zurich		Switzerland
79	Heartlands Hospital	Birmingham		United Kingdom
80	Addenbrookes	Cambridge		United Kingdom
81	Great Western Hospital	Swindon		United Kingdom

Sponsors and Collaborators

• European Society for Blood and Marrow Transplantation
• Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• Celgene Corporation

Investigators

• Principal Investigator: Laurent Garderet, MD, Hôpial Saint Antoine, Paris, France - <[e-mail]>

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Sponsor's website

Publications

None provided.

• Responsible Party: European Society for Blood and Marrow Transplantation
• ClinicalTrials.gov Identifier: NCT00256776
• Other Study ID Numbers: EudraCT: 2005-001628-35; EBMT-CLWP: 42206611
• First Posted: Nov 22, 2005
• Last Update Posted: Oct 18, 2021
• Last Verified: Sep 1, 2021

• Keywords provided by European Society for Blood and Marrow Transplantation: Multiple Myeloma; Velcade; Autologous transplantation; Relapse; Disease progress
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Thalidomide; Dexamethasone; Bortezomib

Study Results

Participant Flow

Recruitment Details	FPI 08-Jul-2005 LPI 21-Jun-2010

Arm/Group Title	Thal + Dex + Velcade	Thal + Dex
Arm/Group Description	Velcade (Bortezomib) Thalidomide Dexamethasone Allocated to treatment (n=135) Received allocated treatment (n=135)	Standard treatment Thalidomide Dexamethasone Allocated to treatment (n=134) Received allocated treatment (n=134)
Period Title: Overall Study
STARTED	135	134
COMPLETED	52	54
NOT COMPLETED	83	80

Baseline Characteristics

Arm/Group Title	Thal + Dex + Velcade	Thal + Dex	Total
Arm/Group Description	Velcade (Bortezomib) Thalidomide Dexamethasone Allocated to treatment (n=135) Received allocated treatment (n=135)	Standard treatment Thalidomide Dexamethasone Allocated to treatment (n=134) Received allocated treatment (n=134)	Total of all reporting groups
Overall Participants	135	134	269
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	105 77.8%	97 72.4%	202 75.1%
>=65 years	30 22.2%	37 27.6%	67 24.9%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60	62.6	61.2
Sex: Female, Male (Count of Participants)
Female	49 36.3%	51 38.1%	100 37.2%
Male	86 63.7%	83 61.9%	169 62.8%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Austria	5 3.7%	3 2.2%	8 3%
Belgium	9 6.7%	14 10.4%	23 8.6%
Hungary	5 3.7%	6 4.5%	11 4.1%
Czechia	5 3.7%	3 2.2%	8 3%
Italy	10 7.4%	11 8.2%	21 7.8%
United Kingdom	0 0%	1 0.7%	1 0.4%
Israel	1 0.7%	0 0%	1 0.4%
France	71 52.6%	68 50.7%	139 51.7%
Switzerland	11 8.1%	8 6%	19 7.1%
Germany	18 13.3%	20 14.9%	38 14.1%

Outcome Measures

1. Primary Outcome

Title	Median Time to Progression (TTP)
Time Frame	3 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Thal + Dex + Velcade	Thal + Dex
Arm/Group Description	Velcade (Bortezomib) Thalidomide Dexamethasone	Standard treatment Thalidomide Dexamethasone
Measure Participants	135	134
Median (95% Confidence Interval) [months]	19.5	13.8

2. Secondary Outcome

Title	Progression Free Survival
Time Frame	3 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Thal + Dex + Velcade	Thal + Dex
Arm/Group Description	Velcade (Bortezomib) Thalidomide Dexamethasone Median time to progression (primary end point): 19.5 months	Standard treatment Thalidomide Dexamethasone Median time to progression (primary end point): 13.8 months
Measure Participants	135	134
Median (95% Confidence Interval) [months]	18.3	13.6

3. Secondary Outcome

Title	Overall Survival (Interval Between Date of Randomization and Death From Any Cause
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Response Rate (Proportion of Subjects Who Achieve Complete, Partial, or Minimal Response)
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Thal + Dex + Velcade		Thal + Dex
Arm/Group Description	Velcade (Bortezomib) Thalidomide Dexamethasone Allocated to treatment (n=135) Received allocated treatment (n=135)		Standard treatment Thalidomide Dexamethasone Allocated to treatment (n=134) Received allocated treatment (n=134)
All Cause Mortality
	Thal + Dex + Velcade		Thal + Dex
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Thal + Dex + Velcade		Thal + Dex
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	58/135 (43%)		45/134 (33.6%)
General disorders
Various other SAEs	31/135 (23%)	46	30/134 (22.4%)	39
Hepatobiliary disorders
Pancreatitis	1/135 (0.7%)	1	0/134 (0%)	0
Infections and infestations
Infection	16/135 (11.9%)	21	4/134 (3%)	4
Musculoskeletal and connective tissue disorders
Asthenia	1/135 (0.7%)	1	1/134 (0.7%)	1
Bone Pain	1/135 (0.7%)	2	0/134 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Carcinoma	1/135 (0.7%)	1	2/134 (1.5%)	2
Nervous system disorders
Neuropathy	3/135 (2.2%)	3	0/134 (0%)	0
Renal and urinary disorders
Renal Failure	3/135 (2.2%)	3	1/134 (0.7%)	1
Reproductive system and breast disorders
Lung Carcinoma	0/135 (0%)	0	2/134 (1.5%)	2
Respiratory, thoracic and mediastinal disorders
Respiratory Distress	1/135 (0.7%)	1	0/134 (0%)	0
Pneumonia	15/135 (11.1%)	15	7/134 (5.2%)	7
Bronchitis	0/135 (0%)	0	2/134 (1.5%)	2
Pulmonary Embolism	6/135 (4.4%)	6	2/134 (1.5%)	3
Vascular disorders
Vascular Pain	0/135 (0%)	0	1/134 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Thal + Dex + Velcade		Thal + Dex
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/135 (0%)		0/134 (0%)

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.