Clinical trial NCT00908232: Treatment With Velcade (Bortezomib) Plus Dexamethasone (VD) or VD Plus Cyclophosphamide or VD Plus Lenalidomide in Patients With Multiple Myeloma Stabilized After 4 Cycles of VD
Official title: Efficacy and Safety of Velcade Plus Dexamethasone (VD), VD+Cyclophosphamide or VD Plus Lenalidomide in MMY Patients Who Are Refractory or Have Relapsed After Their Primary Therapy for MMY and Have Achieved Stable Disease After 4 Cycles of VD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: multiple myeloma
bortezomib
hematology
bone marrow cancer
immunoglobulin
refractory
progression
dexamethasone
lenalidomide
cyclophosphamide
Lead sponsor: Janssen-Cilag International NV
Sponsor class: INDUSTRY
First posted: 2009-05-25
Enrollment: 163
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to test the effectiveness and safety of adding cyclophosphamide or lenalidomide to the VD combination in the treatment of patients with multiple myeloma that have achieved a stable response after 4 initial cycles of treatment with VD. Multiple myeloma is the second most common cancer of the blood. Bortezomib disrupts the life cycle of the cell, affecting numerous biologic pathways, including those related to growth and survival of cancer cells.

Detailed description: It has been shown that quality of response corresponds with clinical benefit. Stable disease is not regarded as a satisfactory result of therapy for relapsed and refractory multiple myeloma. However, there is no consensus if, when and how treatment should be continued or changed in the case of stable disease.

There are different strategies of achieving an optimal quality of response in relapsed and refractory multiple myeloma. One is to treat for a longer duration with one regimen. The alternative path can be a sequential approach adding another agent to the initial regimen depending on the outcome of therapy after a defined treatment period. These two principles will be evaluated in the present study.

Both Cyclophosphamide and Lenalidomide have proven to be efficacious in multiple myeloma and combinations of both agents with bortezomib and Dexamethasone have been shown to be active and tolerable.

In this study patients with relapsed/progressive or refractory multiple myeloma will start treatment with bortezomiib and Dexamethasone. Response will be evaluated after four cycles. Patients with complete, very good partial response or partial response will continue treatment as initiated. Patients with stable disease will either continue treatment with the bortezomib/Dexamethasone combination for another four cycles or will receive Cyclophosphamide or Lenalidomide as an additional third agent for another four cycles.

Patients with multiple myeloma that are refractory to or have relapsed/progressed after primary treatment for multiple myeloma will be enrolled in the study. All patients will receive a combination of bortezomib plus dexamethasone for a total of four cycles. Based on the response to this treatment, further study treatment is customized. Patients with a complete, a very good partial or a partial response will continue to receive bortezomib and Dexamethasone for a maximum additional four cycles, to an overall maximum of eight cycles. Patients achieving stable disease, as defined by International Myeloma Working Group 2006 (IMWG 2006) response criteria, will undergo a central randomisation to continue treatment with VD or VD plus cyclophosphamide or VD plus lenalidomide. Patients with progressive disease will go off study treatment. After randomisation, patients will receive therapy for up to four additional treatment cycles, to an overall maximum of eight cycles. Each cycle will consist of three weeks treatment. There will be a long-term follow-up period with monthly visits until relapse or progressive disease. Thereafter follow-up for survival will be continued by at least a phone call every other month. This will be performed for all patients until the last patient was treated and followed up for 1 year.

Safety will be assessed by the monitoring of adverse events, physical examination (including neurological/peripheral neurological examinations), pulmonary examinations, vital signs measurements, and clinical laboratory tests.

Patients will be treated in a 3-week cycle, up to a maximum of 8 cycles bortezomib 1.3 mg/m2 will be administered on day 1, 4, 8 and 11 as i.v. bolus infusion.

Dexamethasone 20 mg po will be administered on days 1, 2, 4, 5, 8, 9, 11, 12. Dexamethasone will be administered as 2 tables of 8 mg plus 1 tablet of 4 mg Cyclophosphamide 500 mg po will be administered as 10 tablets of 50 mg on day 1, 8, 15 Lenalidomide will be administered as once daily 10 mg tablet from day 1 to 14

Eligibility criteria: Inclusion Criteria:

* Patient has relapsed/progressed or is refractory for multiple myeloma following 1 previous line of therapy
* Measurable secretory multiple myeloma: measurable disease for secretory multiple myeloma is defined by at least one of the following measurements: serum monoclonal protein greater than or equal to 1 g/dl (\> 10 gm/l) \[10g/l\], urine M-protein of ≥200 mg/24 hours
* Patient has a Karnofsky performance status of ≥ 60
* Patient has a life expectancy estimated at screening of at least 6 months
* Patient fulfills defined pretreatment laboratory requirements at and within 14 days before baseline

Exclusion Criteria:

* Patient received more than 1 previous line of therapy for multiple myeloma
* Patient has known allergy or hypersensitivity to bortezomib, Dexamethasone and/or Cyclophosphamide and/or Lenalidomide or any of the constituent compounds such as boron, mannitol, or lactose
* Patient has oligosecretory or non-secretory multiple myeloma
* Patient received nitrosoureas or any other chemotherapy (including thalidomide), clarithromycin, interferon within 6 weeks before enrolment. Note: subjects can have received thalidomide or interferon as maintenance therapy, according to local standard of care
* Patient received corticosteroids (\> 10 mg/day prednisone or equivalent) within 3 weeks before enrolment. Note: subjects can have received steroids (dexamethasone or equivalent) as maintenance therapy according to local standard of care. In addition, subjects can have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy within 3 weeks prior to study entry.

Primary outcomes:
measure: Overall Best Confirmed Response
timeFrame: Prior to treatment at day 1 of each cycle and at the end of treatment (day 21 of cycle 8), up to 168 days
Secondary outcomes:
measure: Median Time to First Confirmed Response
timeFrame: At Day 1 of each treatment cycle, at the End of Treatment visit until there is evidence of Progressive Disease or relapse from Complete Response (CR), up to 168 days
measure: Progression Free Survival
timeFrame: At Day 1 of each treatment cycle, at the End of Treatment visit until there is evidence of Progressive Disease or relapse from Complete Response (CR). Median Follow-Up of 16.9 months
measure: Time to Progression
timeFrame: At Day 1 of each treatment cycle, at the End of Treatment visit until there is evidence of Progressive Disease or relapse from Complete Response (CR), Median Follow-up of 16.9 months
measure: One Year Survival
timeFrame: At each visit from baseline to end of treatment. After treatment, monthly visit until progression or relapse or until the start of alternative MMY therapy, up to 1 year
measure: Overall Survival
timeFrame: At each visit from baseline to end of treatment. After treatment, monthly visit until progression or relapse or until the start of alternative MMY therapy. Further follow up by monthly phone call until the last patient was treated and followed for 1 year
Other outcomes:
Locations:
city: Bordeaux
country: France
city: Le Mans Cedex 2
country: France
city: Lille Cedex
country: France
city: Tours Cedex 9
country: France
city: Duisburg
country: Germany
city: Essen
country: Germany
city: Frankfurt An Der Oder
country: Germany
city: Leipzig
country: Germany
city: München
country: Germany
city: Mÿnchen
country: Germany
city: Oldenburg
country: Germany
city: Ulm
country: Germany
city: Athens
country: Greece
city: Patra
country: Greece
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Miskolc
country: Hungary
city: Nyiregyhaza
country: Hungary
city: Szeged
country: Hungary
city: Kaunas
country: Lithuania
city: Klaipeda
country: Lithuania
city: Vilnius Lt
country: Lithuania
city: Bialystok
country: Poland
city: Katowice
country: Poland
city: Kraków
country: Poland
city: Lodz
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Belgrade
country: Serbia
city: Nis
country: Serbia
city: Novi Sad
country: Serbia
city: Sremska Kamenica
country: Serbia
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Toledo
country: Spain
city: Valencia
country: Spain
city: Ankara
country: Turkey
city: Istambul
country: Turkey
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
city: Bath
country: United Kingdom
city: Edinburgh
country: United Kingdom
city: London
country: United Kingdom
Study officials:
affiliation: Janssen-Cilag International NV
name: Janssen-Cilag International NV Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Dimopoulos MA, Orlowski RZ, Facon T, Sonneveld P, Anderson KC, Beksac M, Benboubker L, Roddie H, Potamianou A, Couturier C, Feng H, Ataman O, van de Velde H, Richardson PG. Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma. Haematologica. 2015 Jan;100(1):100-6. doi: 10.3324/haematol.2014.112037. Epub 2014 Sep 26.