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

• ClinicalTrials.gov Identifier: NCT00813150
• Recruitment Status: Completed
• First Posted: December 22, 2008
• Results First Posted: August 15, 2014
• Last Update Posted: August 15, 2014
• Sponsor: Janssen-Cilag G.m.b.H
• Information provided by (Responsible Party): Janssen-Cilag G.m.b.H

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Multiple Myeloma	Drug: Dexamethasone; Drug: Bortezomib; Drug: Cyclophosphamide	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Study Start Date: January 2009
• Actual Primary Completion Date: January 2013
• Actual Study Completion Date: January 2013

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

Primary Outcome Measures :

1. 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) ]
   '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 :

1. 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) ]
   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.
2. Overall Survival (OS) [ Time Frame: From the date of randomization until Month 49 ]
   Time interval in months time from randomisation to death from any cause.
3. 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 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kropff M, Vogel M, Bisping G, Schlag R, Weide R, Knauf W, Fiechtner H, Kojouharoff G, Kremers S, Berdel WE. Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study. Ann Hematol. 2017 Nov;96(11):1857-1866. doi: 10.1007/s00277-017-3065-z. Epub 2017 Sep 14.

• Responsible Party: Janssen-Cilag G.m.b.H
• ClinicalTrials.gov Identifier: NCT00813150
• Other Study ID Numbers: CR015247; 26866138MMY3022 ( Other Identifier: Janssen-Cilag G.m.b.H, Germany ); 2008-003213-27 ( EudraCT Number )
• First Posted: December 22, 2008
• Results First Posted: August 15, 2014
• Last Update Posted: August 15, 2014
• Last Verified: July 2014

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; Dexamethasone; Cyclophosphamide; Bortezomib; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents