Bendamustine, Lenalidomide (Revlimid®) and Dexamethasone (BRd) as 2nd-line Therapy for Patients With Relapsed or Refractory Multiple Myeloma (BRd)
Primary Purpose
Multiple Myeloma
Status
Completed
Phase
Phase 2
Locations
Switzerland
Study Type
Interventional
Intervention
Bendamustine
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Myeloma focused on measuring Relapsed / refractory multiple myeloma, 2nd line treatment
Eligibility Criteria
Inclusion Criteria:
- Written informed consent
- Patients with first relapsed or refractory multiple myeloma (including patients with relapse after high dose chemotherapy followed by autologous stem cell transplantation) who have received no more than one prior line of anti-myeloma treatment
- Treatment with a lenalidomide/ dexamethasone-based 2nd-line regimen is indicated and intended
Measurable disease as defined by at least one of the following 3 measurements
- serum monoclonal protein level ≥ 1 g/dl (≥ 10 g/l) or
- urine M-protein level ≥ 200 mg/24hours or
- serum FLC assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l) provided serum FLC ratio is abnormal
- ECOG performance status 0, 1, or 2
- Age ≥ 18 years
- All previous cancer therapy (except corticosteroid therapy), including radiation, cytostatic therapy and surgery, must have been discontinued at least 4 weeks prior to treatment in this study.
- No prior treatment with a bendamustine-containing regimen allowed
- Prior treatment with lenalidomide is allowed if the treatment is completed > 12 month prior to study entry and the patient responded to prior lenalidomide treatment
Adequate hematological values:
- absolute neutrophil count ≥ 1.5 x 109/L
- platelets ≥ 100 x 109/L
- hemoglobin > 80 g/L, unless considered to be caused by the underlying hematologic malignancy, based on the investigator's clinical judgement
Adequate hepatic function:
- total bilirubin < 1.2 mg/dL
- AST (SGOT) ≤ 2.5 x ULN
Adequate renal function:
o calculated creatinine clearance > 50 ml/min, according to the formula of Cockcroft-Gault
Disease free of prior malignancies for > 5 years unless the patient
- has been treated with a curative intent and is considered to be in complete remission for ≥2 years prior to study enrolment
or has a curatively-treated
- basal cell/ squamous cell carcinoma of the skin,
- carcinoma "in situ"of the cervix,
- ductal breast carcinoma in situ with complete surgical resection (i.e. negative margins),
- medullary or papillary thyroid tumor
- or low grade, early stage localized prostate cancer treated surgically with curative intent
Exclusion Criteria:
- Pregnant or breast feeding females
- Any prior use of bendamustine
- Patients who are unable or unwillingly to undergo antithrombotic therapy
- Any serious underlying medical condition (at the judgment of the investigator) which impairs the ability of the patient to participate in the trial (e.g. active autoimmune disease, uncontrolled diabetes, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric disorder)
- Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she would participate in the study or any condition significantly confounding the ability to interpret data from the study, based on the local investigator's judgement
- Severe cardiovascular disease, including myocardial infarction within 6 months before study entry, New York Heart Association Class III or IV heart failure, uncontrolled angina or severe uncontrolled ventricular arrhythmias (≥ Lown 3)
- Use of any other experimental drug or therapy/ treatment in a clinical trial within 30 days prior to trial entry
- Known hypersensitivity to study drug(s) or hypersensitivity to any other component of the study drugs
- Any concurrent antineoplastic therapy with chemotherapeutic agents or biologic agents or radiation therapy
- Any major surgical procedure within 30 days prior to study therapy
- Known chronic hepatitis B or C, known HIV infection
- Jaundice or any other severe damage of the liver parenchyma
- Any contraindication for the treatment with bendamustine, lenalidomide, dexamethasone and / or pegfilgrastim in accordance with the appropriate SmPCs
- Any other concomitant drugs contraindicated for use with the study drugs according to the national health authorities
Sites / Locations
- Kantonsspital St. Gallen
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Bendamustine
Arm Description
All patients are treated with bendamustine in combination with lenalidomide and dexamethasone for a maximum of 6 cycles.
Outcomes
Primary Outcome Measures
Efficacy (combined CR-/VGPR-rate) achieved during the induction treatment phase or within four weeks after the last administration of six induction cycles of the BRd regimen
Secondary Outcome Measures
Objective response rates (sCR, CR, VGPR, PR, MR)
Best response (sCR, CR, VGPR, PR, MR)
Time to progression (TTP)
Overall survival (OS)
Safety and tolerability
Type, frequency, severity, and relationship of adverse events to study therapy
According to NCI CTCAE v4.0
Full Information
NCT ID
NCT01701076
First Posted
September 27, 2012
Last Updated
August 23, 2016
Sponsor
Cantonal Hospital of St. Gallen
Collaborators
Celgene Corporation, Mundipharma Research GmbH & Co KG, Mundipharma Medical Company, Amgen
1. Study Identification
Unique Protocol Identification Number
NCT01701076
Brief Title
Bendamustine, Lenalidomide (Revlimid®) and Dexamethasone (BRd) as 2nd-line Therapy for Patients With Relapsed or Refractory Multiple Myeloma
Acronym
BRd
Official Title
An Open, Multicentric Phase II Trial to Evaluate the Efficacy and Safety of Bendamustine, Lenalidomide (Revlimid®) and Dexamethasone (BRd) as 2nd-line Therapy for Patients With Relapsed or Refractory Multiple Myeloma
Study Type
Interventional
2. Study Status
Record Verification Date
August 2016
Overall Recruitment Status
Completed
Study Start Date
March 2012 (undefined)
Primary Completion Date
February 2016 (Actual)
Study Completion Date
February 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Cantonal Hospital of St. Gallen
Collaborators
Celgene Corporation, Mundipharma Research GmbH & Co KG, Mundipharma Medical Company, Amgen
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Almost all patients with multiple myeloma who survive initial treatment will eventually relapse and require further therapy.
Background: Treatment with lenalidomide and dexamethasone has proven efficacy in two large randomized trials (MM-009 and MM-010) leading to a time to progression (TTP) of 17.1 months for patients with only one prior therapy and a TTP of 10.6 months for 2 and more prior therapies, respectively [1-3]. Continuous treatment with lenalidomide and dexamethasone until disease progression is therefore considered a standard therapy for second line treatment in multiple myeloma patients. However, only a relatively low rate of high quality response (CR, complete response and VGPR, very good partial response) is achieved. High quality responses are associated with with improved progression-free survival and overall survival [4].
Trial: The aim of this trial is to improve high quality response rates for patients with relapsed or refractory multiple myeloma in the 2nd line treatment. This aim shall be achieved by the addition a third anti-myeloma drug (bendamustine) to the established backbone of lenalidomide/ dexamethasone.
Treatment regimen:
Induction Treatment Phase: Cycles 1-6 Bendamustine 75mg/m2/d day 1 and 2, lenalidomide 25mg/d 1-21, dexamethasone 40mg / 20mg (for patients > 75years) d 1, 8, 15, 22.
Maintenance Treatment Phase: Cycles 7-18 lenalidomide 25mg/d 1-21, dexamethasone 40mg / 20mg (for patients > 75 years) d 1, 8, 15, 22.
Due to hematoxicity of bendamustine and lenalidomide, administration of pegfilgrastim is mandatory in the induction treatment phase (BRd-regimen)for all patients experiencing severe neutropenia.
The aim of this study is to achieve high quality response rates (CR, VGPR) of ≥ 40%. If this aim is achieved, the treatment of bendamustine in combination with the established lenalidomide/ dexamethasone regimen will be considered promising.
Besides efficacy, the safety of this three-drug regimen is evaluated in this trial.
Detailed Description
Assessments for efficacy / response evaluation:
M-protein quantitation in serum and 24 h urine collection samples by serum- and urine protein electrophoresis
Quantitation of immunoglobulin levels by nephelometry
Serum and urine immunofixation
Free light chain concentrations and ratio in the serum
Plasma cell percentage in the bone marrow by conventional cytology and biopsy with immunohistochemistry
Radiologic assessments of the skeleton
Response criteria: Response will be assessed according to IMWG criteria
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma
Keywords
Relapsed / refractory multiple myeloma, 2nd line treatment
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Bendamustine
Arm Type
Experimental
Arm Description
All patients are treated with bendamustine in combination with lenalidomide and dexamethasone for a maximum of 6 cycles.
Intervention Type
Drug
Intervention Name(s)
Bendamustine
Other Intervention Name(s)
Lenalidomide, Dexamethasone, Pegfilgrastim
Intervention Description
Induction treatment phase (cycle 1-6):
Bendamustine 75 mg/m2 i.v day 1 and 2
Lenalidomide 25 mg p.o. day 1-21
Dexamethasone 40/20 mg p.o., day 1, 8, 15, 22
Pegfilgrastim 6 mg s.c., day 3 in case of severe neutropenia
Maintenance treatment phase (cycles 7-18):
Lenalidomide 25 mg p.o. day 1-21
Dexamethasone 40/20 mg p.o., day 1, 8, 15, 22
Primary Outcome Measure Information:
Title
Efficacy (combined CR-/VGPR-rate) achieved during the induction treatment phase or within four weeks after the last administration of six induction cycles of the BRd regimen
Time Frame
Every 4 weeks up to 7 months
Secondary Outcome Measure Information:
Title
Objective response rates (sCR, CR, VGPR, PR, MR)
Time Frame
Every 4 weeks up to 7 months
Title
Best response (sCR, CR, VGPR, PR, MR)
Time Frame
Every 4 weeks up to 36 months
Title
Time to progression (TTP)
Time Frame
Every 4 weeks up to 36 months
Title
Overall survival (OS)
Time Frame
Every 8 weeks up to 36 months
Title
Safety and tolerability
Description
Type, frequency, severity, and relationship of adverse events to study therapy
According to NCI CTCAE v4.0
Time Frame
Every 4 weeks until 30 days after completion of study treatment
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Written informed consent
Patients with first relapsed or refractory multiple myeloma (including patients with relapse after high dose chemotherapy followed by autologous stem cell transplantation) who have received no more than one prior line of anti-myeloma treatment
Treatment with a lenalidomide/ dexamethasone-based 2nd-line regimen is indicated and intended
Measurable disease as defined by at least one of the following 3 measurements
serum monoclonal protein level ≥ 1 g/dl (≥ 10 g/l) or
urine M-protein level ≥ 200 mg/24hours or
serum FLC assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l) provided serum FLC ratio is abnormal
ECOG performance status 0, 1, or 2
Age ≥ 18 years
All previous cancer therapy (except corticosteroid therapy), including radiation, cytostatic therapy and surgery, must have been discontinued at least 4 weeks prior to treatment in this study.
No prior treatment with a bendamustine-containing regimen allowed
Prior treatment with lenalidomide is allowed if the treatment is completed > 12 month prior to study entry and the patient responded to prior lenalidomide treatment
Adequate hematological values:
absolute neutrophil count ≥ 1.5 x 109/L
platelets ≥ 100 x 109/L
hemoglobin > 80 g/L, unless considered to be caused by the underlying hematologic malignancy, based on the investigator's clinical judgement
Adequate hepatic function:
total bilirubin < 1.2 mg/dL
AST (SGOT) ≤ 2.5 x ULN
Adequate renal function:
o calculated creatinine clearance > 50 ml/min, according to the formula of Cockcroft-Gault
Disease free of prior malignancies for > 5 years unless the patient
has been treated with a curative intent and is considered to be in complete remission for ≥2 years prior to study enrolment
or has a curatively-treated
basal cell/ squamous cell carcinoma of the skin,
carcinoma "in situ"of the cervix,
ductal breast carcinoma in situ with complete surgical resection (i.e. negative margins),
medullary or papillary thyroid tumor
or low grade, early stage localized prostate cancer treated surgically with curative intent
Exclusion Criteria:
Pregnant or breast feeding females
Any prior use of bendamustine
Patients who are unable or unwillingly to undergo antithrombotic therapy
Any serious underlying medical condition (at the judgment of the investigator) which impairs the ability of the patient to participate in the trial (e.g. active autoimmune disease, uncontrolled diabetes, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric disorder)
Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she would participate in the study or any condition significantly confounding the ability to interpret data from the study, based on the local investigator's judgement
Severe cardiovascular disease, including myocardial infarction within 6 months before study entry, New York Heart Association Class III or IV heart failure, uncontrolled angina or severe uncontrolled ventricular arrhythmias (≥ Lown 3)
Use of any other experimental drug or therapy/ treatment in a clinical trial within 30 days prior to trial entry
Known hypersensitivity to study drug(s) or hypersensitivity to any other component of the study drugs
Any concurrent antineoplastic therapy with chemotherapeutic agents or biologic agents or radiation therapy
Any major surgical procedure within 30 days prior to study therapy
Known chronic hepatitis B or C, known HIV infection
Jaundice or any other severe damage of the liver parenchyma
Any contraindication for the treatment with bendamustine, lenalidomide, dexamethasone and / or pegfilgrastim in accordance with the appropriate SmPCs
Any other concomitant drugs contraindicated for use with the study drugs according to the national health authorities
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ulrich Mey, MD
Organizational Affiliation
Kantonsspital Graubünden
Official's Role
Study Chair
Facility Information:
Facility Name
Kantonsspital St. Gallen
City
St. Gallen
ZIP/Postal Code
9000
Country
Switzerland
12. IPD Sharing Statement
Citations:
PubMed Identifier
18032763
Citation
Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007 Nov 22;357(21):2133-42. doi: 10.1056/NEJMoa070596.
Results Reference
background
PubMed Identifier
18032762
Citation
Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foa R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007 Nov 22;357(21):2123-32. doi: 10.1056/NEJMoa070594. Erratum In: N Engl J Med. 2009 Jul 30;361(5):544.
Results Reference
background
PubMed Identifier
19626046
Citation
Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. doi: 10.1038/leu.2009.147. Epub 2009 Jul 23.
Results Reference
background
PubMed Identifier
19638622
Citation
Harousseau JL, Attal M, Avet-Loiseau H. The role of complete response in multiple myeloma. Blood. 2009 Oct 8;114(15):3139-46. doi: 10.1182/blood-2009-03-201053. Epub 2009 Jul 28.
Results Reference
background
PubMed Identifier
22451423
Citation
Lentzsch S, O'Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, Burt S, Boyiadzis M, Roodman GD, Mapara MY, Agha M, Waas J, Shuai Y, Normolle D, Zonder JA. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012 May 17;119(20):4608-13. doi: 10.1182/blood-2011-12-395715. Epub 2012 Mar 26.
Results Reference
background
Citation
Pönisch W, Heyn S, Wagner I, et al. Combined Bendamustine, Prednisolone and Lenalidomide (RBP) In Refractory or Relapsed Multiple Myeloma. First Results of a Phase I Clinical Trial. Blood, Nov 2010; 116: 1971
Results Reference
background
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Bendamustine, Lenalidomide (Revlimid®) and Dexamethasone (BRd) as 2nd-line Therapy for Patients With Relapsed or Refractory Multiple Myeloma
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