Study of Bortezomib and Dexamethasone With or Without Cyclophosphamide in Patients With Relapsed or Not Controllable Multiple Myeloma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Janssen-Cilag G.m.b.H
ClinicalTrials.gov Identifier:
NCT00813150
First received: December 18, 2008
Last updated: July 31, 2014
Last verified: July 2014
  Purpose

The purpose of this study is to compare bortezomib, dexamethasone and cyclophosphamide to bortezomib and dexamethasone alone for primary refractory or relapsed multiple myeloma.


Condition Intervention Phase
Multiple Myeloma
Drug: Dexamethasone
Drug: Bortezomib
Drug: Cyclophosphamide
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase III Study on Bortezomib and Low-Dose Dexamethasone With or Without Continuous Low-Dose Oral Cyclophosphamide for Primary Refractory or Relapsed Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Janssen-Cilag G.m.b.H:

Primary Outcome Measures:
  • Time to Progression of Disease [ Time Frame: From the date of randomization until the disease progression or participant's death from any cause whichever occurred first, as assessed up to 72 weeks after end of treatment visit (ie, 46 days after last dose of study medication) ] [ Designated as safety issue: No ]
    'Median time to progression of disease is assessed according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of >=25% from lowest level in Serum M-component or (the absolute increase must be >=0.5 gram per deciliter [g/dL]); Urine M component or (the absolute increase must be >=200 milligram per 24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase >10 mg/dL. Bone marrow plasma cell percentage >=10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing. Development of hypercalcemia. Participants who died or dropped out due to any reason without progression will be censored with the day of death or drop-out, respectively and who are alive at the end of the study without any progression was censored with the last available date.


Secondary Outcome Measures:
  • Progression-Free Survival (PFS) [ Time Frame: From the date of randomization until the disease progression or participant's death from any cause whichever occured first, as assessed up to 72 weeks after end of treatment visit (ie, 46 days after last dose of study medication) ] [ Designated as safety issue: No ]
    PFS is defined as time from randomization to myeloma progression according to International Myeloma Working Group (IMWG) criteria or death from any cause. IMWG criteria: increase of ≥25 percent from lowest response level in Serum M-component and/or (the absolute increase must be ≥0.5 g/dL) Urine M-component and/or (the absolute increase must be ≥200 mg/24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: the absolute percent must be ≥10 percent. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65mmol/L) that can be attributed solely to the plasma cell proliferative disorder. PFS included disease progression as well as death.

  • Overall Survival (OS) [ Time Frame: From the date of randomization until Month 49 ] [ Designated as safety issue: No ]
    Time interval in months time from randomisation to death from any cause.

  • Overall Response Rate (ORR) - International Myeloma Working Group (IMWG) Response Criteria [ Time Frame: Up to 46 days after last bortezomib dose, or as soon as possible after early discontinuation of study treatment or before start of alternative anti-myeloma therapy ] [ Designated as safety issue: No ]
    Percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) is reported in the below table. IMWG criteria- CR: Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow; sCR: CR+Normal free light chain ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescencec; PR: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90%; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24 hour.


Enrollment: 96
Study Start Date: January 2009
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vd (bortezomib + dexamethasone)

Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days

1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle.

Drug: Dexamethasone
Type=exact number, number=20, unit=mg, form=tablet, route=oral. The patients will receive 20 mg of dexamethasone on days 1+2,4+5,8+9,11+12 for 21 days for 8 cycles.
Drug: Bortezomib
Type=exact number, number=1.3, unit=mg, form=injection, route=intravenous. The patients will receive 1.3mg/m2 on days 1,4,8,11 for 21 days for 8 cycles.
Active Comparator: Vcd (bortezomib + low-dose dexamethasone + cyclophosphamide)
Participants received bortezomib at a dose of 1.3 mg/m² body surface area (BSA) for eight 3-week cycles. Within each cycle it was administered twice weekly (on Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 through 21). They received single oral doses of 20 mg dexamethasone on Days 1 and 2, 4 and 5, 8 and 9, and 11 and 12 of each cycle and single oral doses of 50 mg cyclophosphamide on a once daily basis from Day 1, Cycle 1 continuously until Day 21, Cycle 8.
Drug: Dexamethasone
Type=exact number, number=20, unit=mg, form=tablet, route=oral. The patients will receive 20 mg of dexamethasone on days 1+2,4+5,8+9,11+12 for 21 days for 8 cycles.
Drug: Bortezomib
Type=exact number, number=1.3, unit=mg, form=injection, route=intravenous. The patients will receive 1.3mg/m2 on days 1,4,8,11 for 21 days for 8 cycles.
Drug: Cyclophosphamide
Type=exact number, number=50, unit=mg, form=tablet, route=oral. The patients will receive 50 mg of cyclophosphamide once daily continuously from cycle 1 to 8.

Detailed Description:

This is a prospective, multi-centre, randomized (the study drug is assigned by chance), controlled, open-label (all people involved in the study know the identity of the assigned drug), parallel (each group of patients will be treated at the same time) group phase III study to determine the efficacy of the standard therapy of bortezomib and low dose dexamethasone in combination with or without continuous low dose oral cyclophosphamide for primary refractory or relapsed myeloma patients (1st - 3rd relapse). The study will consist of screening period, which may last from day -14 until day -1 before application of the first dose of bortezomib (on cycle 1, day 1), treatment phase begins on cycle 1 day 1 and continues until completion or discontinuation of all study drugs and follow-up phase. All patients will be followed up after end of treatment regardless of their response. Eligible patients will be randomized in 1:1 ratio to receive either treatment arms (Group A: receiving bortezomib plus dexamethasone or Group B receiving bortezomib plus dexamethasone plus cyclophosphamide). Patients will receive up to eight 3-weeks treatment cycles, unless they experience either unacceptable toxicity or if the patients request to withdraw from the study. The maximum number of cycles is dependent on patient response and investigator's discretion. It is recommended that patients with a confirmed complete response (CR) receive 2 additional cycles beyond a confirmation. Patients who do not achieve a CR but a partial response will receive a total of 8 cycles. For patients achieving stable disease it is within the investigator's discretion to continue study treatment beyond 6 cycles, after discussion with the sponsor. After completion of treatment the patients will be followed up every 12 weeks for up to 72 weeks. If the study is still ongoing a further follow up period will be done every 26 weeks until study end, or until the patient reaches progressive disease or start of alternative anti-myeloma therapy, if earlier. In case progressive disease (PD) has already been established during the treatment phase the patients will not enter the follow-up phase. In case of PD or start of alternative anti-myeloma treatment before the end of study the follow-up phase will be discontinued for the patient but the date of death of the patient will be documented (if applicable) before the end of study.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Previously diagnosed with multiple myeloma
  • Primary refractory multiple myeloma or relapsed following 1 to 3 previous lines of therapy
  • Karnofsky performance status must be equal to 60 percentage (ie, better or equal performance than requiring some help and taking care of most personal requirements)
  • Has life expectancy estimated at screening must be of at least 6 months
  • Agrees to protocol-defined use of effective contraception

Exclusion Criteria:

  • Not received more than three previous lines of therapy for multiple myeloma
  • Not received nitrosoureas or any other chemotherapy or immunotherapy or antibody therapy for multiple myeloma within 6 to 8 weeks before enrolment. Plasmapheresis must not be applied within 2 weeks before enrolment
  • Patients with peripheral neuropathy or neuropathic pain of Grade 2 or greater intensity
  • Patients with poorly controlled cardio vascular, vascular, pulmonary, gastro-intestinal, endocrine, neurological, psychiatric, hepatic, renal or metabolic diseases or hematological disorders
  • Not have oligosecretory or non-secretory multiple myeloma
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00813150

Locations
Germany
Augsburg, Germany
Berlin, Germany
Bielefeld, Germany
Bremerhaven, Germany
Darmstadt, Germany
Donauwörth, Germany
Dresden, Germany
Frankfurt, Germany
Halle, Germany
Hamburg, Germany
Hamm, Germany
Hannover, Germany
Hildesheim, Germany
Hof, Germany
Koblenz, Germany
Köln, Germany
Lebach, Germany
Leer, Germany
Lübeck, Germany
Magdeburg, Germany
Mannheim, Germany
Moers, Germany
München, Germany
Münster, Germany
Neunkirchen, Germany
Offenburg, Germany
Oldenburg, Germany
Osnabrück, Germany
Passau, Germany
Porta Westfalica, Germany
Ravensburg, Germany
Rostock, Germany
Saarbrücken, Germany
Singen, Germany
Stuttgart, Germany
Velbert, Germany
Weiden, Germany
Wiesbaden, Germany
Würselen, Germany
Würzburg, Germany
Sponsors and Collaborators
Janssen-Cilag G.m.b.H
Investigators
Study Director: Janssen-Cilag G.m.b.H, Germany Clinical Trial Janssen-Cilag G.m.b.H
  More Information

No publications provided

Responsible Party: Janssen-Cilag G.m.b.H
ClinicalTrials.gov Identifier: NCT00813150     History of Changes
Other Study ID Numbers: CR015247, 26866138MMY3022, 2008-003213-27
Study First Received: December 18, 2008
Results First Received: March 28, 2014
Last Updated: July 31, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices
Germany: Ethics Commission

Keywords provided by Janssen-Cilag G.m.b.H:
Multiple myeloma
Bortezomib
Dexamethasone
Cyclophosphamide
Oncology

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Bortezomib
Dexamethasone
Dexamethasone acetate
Dexamethasone 21-phosphate
BB 1101
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 21, 2014