Busulfan & Melphalan Conditioning for Autologous Stem Cell Transplant (ASCT) and Lenalidomide Maintenance (BuMelMCRN001)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University Health Network, Toronto
Sponsor:
Collaborators:
Princess Margaret Hospital, Canada
Otsuka Pharmaceutical Development & Commercialization, Inc.
Celgene Corporation
Information provided by (Responsible Party):
University Health Network, Toronto
ClinicalTrials.gov Identifier:
NCT01702831
First received: August 29, 2012
Last updated: May 16, 2014
Last verified: May 2014
  Purpose

A number of strategies have been proposed to improve the outcome of ASCT. The three main strategies are to incorporate novel agents into the induction regimen, using maintenance therapy following ASCT and the final strategy is to enhance conditioning regimens.

Investigators would like to explore all these three strategies in this study: Investigators propose to take patients who have had standard novel agent (bortezomib) based induction regimens into this study and then use a dose-adjusted combination of busulfan and melphalan as conditioning regimen and finally Investigators would like to incorporate lenalidomide maintenance post ASCT until disease progression.


Condition Intervention Phase
Multiple Myeloma
Drug: Busulfan
Drug: Melphalan
Drug: Lenalidomide
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Busulfan & Melphalan as Conditioning Regimen for ASCT in Patients Who Received Bortezomib Based Induction for Newly Diagnosed Multiple Myeloma Followed by Lenalidomide Maintenance Until Progression.

Resource links provided by NLM:


Further study details as provided by University Health Network, Toronto:

Primary Outcome Measures:
  • • Minimal Residual Disease (MRD) negativity at day 100 post ASCT [ Time Frame: day 100 post ASCT ] [ Designated as safety issue: No ]
    The conventional immunological markers used to define myeloma disease status have also been a subject of debate recently with some reports suggesting that more accurate disease assessment tools are needed to better decide on management of this disease. One of the most promising assays which is increasingly accepted as a more sensitive indicator of myeloma disease status is the Minimal Residual Disease (MRD) analysis. Therefore, Investigators plan to use MRD analysis as a disease assessment tool throughout this study and will correlate it with conventional myeloma disease assessment tools. Investigators would also like to incorporate a newly developed assay - Heavy lite (HevyLite) Chain assay - which will be done at the same time points as the other disease assessments thereby allowing us to explore the viability of this assay in clinical practice.


Secondary Outcome Measures:
  • • To determine the pattern, positivity (in terms of percentages) or negativity of MRD analysis during lenalidomide maintenance. [ Time Frame: After ASCT at day 100, during maintenance therapy every 3 months at month 6, 9 and 12 after ASCT; and thereafter every 6 months until disease progression and at discontinuation. ] [ Designated as safety issue: No ]
  • • To determine the response rate using conventional immunoglobulin and monoclonal protein-based markers at day 100 post ASCT and best response using lenalidomide maintenance. [ Time Frame: After ASCT at day 100, during maintenance therapy every 3 months at month 6, 9 and 12 after ASCT; and thereafter every 6 months until disease progression and at discontinuation. ] [ Designated as safety issue: No ]
    The response rate (Complete Response, Very Good Partial Response, Partial Response, Minimal Response and Stable Disease) will be assessed by using the European Group for Blood and Marrow Transplantation modified response criteria,with conventional immunoglobulin and monoclonal protein-based markers at day 100 post ASCT and best response using lenalidomide maintenance.

  • • To determine the effectiveness of using the HevyLite Chain assay to assess anti-tumour response at day 100 post ASCT and during lenalidomide maintenance [ Time Frame: After ASCT at day 100, during maintenance therapy every 3 months at month 6, 9 and 12 after ASCT; and thereafter every 6 months until disease progression and at discontinuation. ] [ Designated as safety issue: No ]
    Immunoglobulin (Ig) A kappa, Immunoglobulin (Ig)A lambda, Immunoglobulin (Ig) A kappa/Immunoglobulin (Ig) A lambda ratio; Immunoglobulin (Ig) G Kappa, Immunoglobulin (Ig) G Lambda,Immunoglobulin (Ig) G kappa/Immunoglobulin (Ig) G lambda ratio; Immunoglobulin (Ig) M Kappa, Immunoglobulin (Ig) M Lambda and Immunoglobulin (Ig) M kappa/Immunoglobulin (Ig) M lambda ratio will be measured. These results will be correlated to standard Free Lite Chain assays performed at the same time points listed above.

  • • To determine the toxicity of busulfan and melphalan when used as a high-dose conditioning therapy for ASCT. [ Time Frame: During conditioning therapy for ASCT. For schema option 1 this will be assessed at days -6, -5, -4, -3 and -2 prior ASCT. For schema option 2 this will be assessed at days -7, -6, -5, -4 and -3 prior ASCT. ] [ Designated as safety issue: Yes ]
    Toxicity of busulfan and melphalan will be determined by tracking occurrence of adverse events, serious adverse events and immediately reportable events based on the definitions listed in the protocol section 18.1 The severity of the toxicity will be graded according to the NCI Common Toxicity Criteria for Adverse Effects(CTCAE) version 3.0

  • • To determine the toxicity of lenalidomide maintenance post busulfan and melphalan conditioning ASCT. [ Time Frame: After day 100 post ASCT, during the maintenance therapy every 3 months at month 6, 9 and 12 after ASCT; and thereafter every 6 months until disease progression and at discontinuation. ] [ Designated as safety issue: Yes ]
    Toxicity of lenalidomide maintenance will be determined by tracking occurrence of adverse events, serious adverse events and immediately reportable events based on the definitions listed in the protocol section 18.1 The severity of the toxicity will be graded according to the NCI CTCAE version 3.0

  • • To determine the progression free survival (PFS) and overall survival (OS) of this program. [ Time Frame: From randomization patients will be followed for PFS every 3 months for the first year after ASCT and then every 6 months until disease progression. After they will be followed every year for O/S until death. ] [ Designated as safety issue: No ]
    These endpoints will be analyzed as time to event variables, which is defined as the time from transplant to death for OS and the time from transplant to the first occurrence of death or disease progression for PFS. The event free probabilities for these endpoints will be estimated by the product limit Kaplan Meier method. Subjects without events will be censored at the last followup for OS and at the last disease evaluation for PFS.


Estimated Enrollment: 78
Study Start Date: March 2013
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: BuMel + lenalidomide Maintenance
I.V. Busulfan + I.V. Melphalan for conditioning prior ASCT, followed by Lenalidomide maintenance at day 100 after ASCT.
Drug: Busulfan
Once daily intravenous (IV) busulfan at a dose of 3.2 mg/kg or equivalent pharmacokinetics directed dose for three consecutive days (days -5 to -3), option 1 OR Once daily intravenous (IV) busulfan at a dose of 3.2mg/kg or equivalent pharmacokinetics directed dose for three consecutive days (days -6 to -4), option 2.
Other Name: Busulfex
Drug: Melphalan
I.V. reduced dose of melphalan (140mg/m2) on day -2, followed by an autologous stem cell transplant on day 0 (day -1 will be a rest day) - this is referred to as "Option 1" dosing schema OR I.V. reduced dose of melphalan (140mg/m2) on day -3 followed by autologous stem cell transplant on day 0 (days -2 and -1 will be rest days). This is referred to as "Option 2"
Other Name: Alkeran
Drug: Lenalidomide
Oral lenalidomide 10mg per day (on all 28 days of a 28 day cycle) for the first three cycles and then escalated to 15 mg daily if clinically appropriate to do so. The lenalidomide maintenance will start on day 100 post ASCT and continue till disease progression.
Other Name: Revlimid

Detailed Description:

STUDY RATIONALE AND PURPOSE:

A number of strategies have been proposed to improve the outcome of ASCT. The three main strategies are to incorporate novel agents into the induction regimen, using maintenance therapy following ASCT and the final strategy is to enhance conditioning regimens.

Investigators would like to explore all these three strategies in this study: Investigators propose to take patients who have had standard novel agent (bortezomib) based induction regimens into this study and then use a dose-adjusted combination of busulfan and melphalan as conditioning regimen and finally Investigators would like to incorporate lenalidomide maintenance post ASCT until disease progression.

The conventional immunological markers used to define myeloma disease status have also been a subject of debate recently with some reports suggesting that more accurate disease assessment tools are needed to better decide on management of this disease. One of the most promising assays which is increasingly accepted as a more sensitive indicator of myeloma disease status is the Minimal Residual Disease (MRD) analysis. Therefore, Investigators plan to use MRD analysis as a disease assessment tool throughout this study and will correlate it with conventional myeloma disease assessment tools. Investigators would also like to incorporate a newly developed assay - Heavy lite (HevyLite) Chain assay - which will be done at the same time points as the other disease assessments thereby allowing us to explore the viability of this assay in clinical practice.

INTERVENTIONS:

Conditioning Regimen IV Busulfan 3.2mg/kg or equivalent pharmacokinetics directed dose once daily as a 3-hour infusion on days -5, -4 and -3 (option 1) or on days -6, -5, -4 (option 2).IV Melphalan 140mg/m2 once on day -2 (for option 1) or day -3 ( for option 2) Maintenance Regimen Oral Lenalidomide 10 mg once daily for 28 days of a 28 days cycle for first three cycles and then dose escalation to 15 mg daily if clinically appropriate to do so.

STUDY ENDPOINTS

Primary:

• MRD negativity at day 100 post ASCT

Secondary:

  • To determine the pattern of MRD analysis during lenalidomide maintenance.
  • To determine the response rate using conventional immunoglobulin-based markers at day 100 post ASCT and best response using lenalidomide maintenance.
  • To determine the effectiveness of using the Heavy lite (HevyLite) Chain assay to assess anti-tumour response at day 100 post ASCT and during lenalidomide maintenance.
  • To determine the toxicity of busulfan and melphalan when used as a high-dose conditioning therapy for ASCT.
  • To determine the toxicity of lenalidomide maintenance post busulfan and melphalan conditioning ASCT.
  • To determine the progression free survival (PFS) and overall survival (OS) of this program.
  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 to 75 years, inclusive.
  2. Study participants must have a diagnosis of multiple myeloma and are eligible for the planned ASCT.
  3. Untreated bone marrow sample was shipped to Princess Margaret Hospital for MRD assay.
  4. Must have been treated with a velcade-based induction regimen. No limit to the number of cycles of induction.
  5. Study participants in whom the minimum stem cell dose of 2.0 x 106 cluster of differentiation (CD)34+ cells/kg has been collected.
  6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
  7. Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test in all females of child-bearing potential (FOCBP).
  8. Ability to provide written informed consent prior to initiation of any study-related procedures, and ability, in the opinion of the Principal Investigator, to comply with all requirements of the study.

Exclusion Criteria:

  1. Myeloma progression at any time since starting initial therapy for myeloma.
  2. Prior treatment history of ASCT for any medical reason.
  3. Prior treatment history of high-dose chemotherapy with stem cell rescue for any medical reason, not limited to myeloma treatment.
  4. Prior treatment with busulfan or gemtuzumab ozogamicin for any reason.
  5. Systemic amyloidosis.
  6. Left ventricular ejection fraction (LVEF) < 45% as measured by either multi-gated acquisition scan (MUGA) or echocardiogram (ECHO) performed within 75 days prior to day of busulfan dose. If cyclophosphamide was used for stem cell harvest, an ECHO or MUGA must be done after the stem cell collection and prior to enrollment to confirm adequate cardiac function.
  7. Uncontrolled arrhythmia or symptomatic cardiac disease at the time of screening.
  8. Symptomatic pulmonary disease, based on Forced Expiratory Volume in 1 Second (FEV1), Forced Vital Capacity (FVC) or Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) < 50% of predicted (corrected for hemoglobin) measured within 75 days prior to day of busulfan dose.
  9. Aspartate transaminase (AST)/alanine transaminase (ALT) ≥ 3 x the upper limit of normal (ULN).
  10. History of elevated total serum bilirubin >2 mg/dL that had been caused by previous chemotherapy at any point, or total bilirubin > 2.0 mg/dL at the time of screening with the exception of Gilbert's disease.
  11. Hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time as International Normalized Ratio (INR) ≥ 2.0 at the time of screening.
  12. Any previous history of fulminant liver failure, cirrhosis, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, and symptomatic biliary disease.
  13. Prior total body irradiation therapy, or radiation therapy directly applied to the liver.
  14. Patients with a known history of hepatitis B or hepatitis C should be on appropriate anti-viral therapy. Even so, these cases must be discussed with the sponsor and approval obtained prior to screening.
  15. Known history of or current HIV infection, or active hepatitis B or c infection or any uncontrolled active infection of any kind at the time busulfan administration.
  16. Serum creatinine >177 umol/L at the time of screening.
  17. Women who are pregnant or lactating.
  18. Current or history of drug and/or alcohol abuse.
  19. Use of other investigational therapies within 30 days of enrollment in this study.
  20. Clinically significant abnormality in medical history or upon examination that might interfere with the outcomes of the study in the opinion of the investigator.
  21. Any patient, who in the opinion of the investigator, should not participate in this study.
  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: NCT01702831

Contacts
Contact: Jesus G Piza, MD. CCRP 416-946-4627 giovanni.piza@uhnresearch.ca
Contact: Mariela Pantoja, Ph.D, CCRP 416-946-4501 ext 3655 Mariela.Pantoja@uhnresearch.ca

Locations
Canada, Alberta
Cross Cancer Institute 11560 University Ave Recruiting
Edmonton, Alberta, Canada, T6G-1Z2
Contact: Annette Yakimyshyn, RN    (780) 989-8169    Annette.yakimyshyn@albertahealthservices.ca   
Contact: Smita Sanghavi, CRC    780-432-8203    smita.sanghavi@albertahealthservices.ca   
Principal Investigator: Chris Venner, MD         
Canada, British Columbia
Vancouver General Hospital, Centennial Pavilion, 6th Floor Recruiting
Vancouver, British Columbia, Canada, V5Z 1M9
Contact: Aria Vassilakis, RN    604-875-4111 ext 69014    aria.vassilakis@bccancer.bc.ca   
Contact: Melanie Lam    604-875-4111 ext 67409    Melanie.lam@bccancer.bc.ca   
Principal Investigator: Kevin Song, MD         
Canada, New Brunswick
Saint John Regional Hospital, 5DN Research Department, 400 University Ave Recruiting
Saint John, New Brunswick, Canada, E2L 4L2
Contact: Kathy Heath, RN    506-648-6697    Kathy.heath@horizonnb.ca   
Contact: Shelly Alward, RN    506-648-6697    shelly.alward@horizonnb.ca   
Principal Investigator: Terrance Comeau, MD         
Canada, Nova Scotia
Queen Elizabeth II Health Sciences Centre. Recruiting
Halifax, Nova Scotia, Canada, B3H 2Y9
Contact: Judith James, RN    902-473-7668    judithA.james@cdha.nshealth.ca   
Contact: Nova Lee Horne, CRC    902-473-7349    Novalee.horne@cdha.nshealth.ca   
Principal Investigator: Darrell White, MD         
Canada, Ontario
London Regional Cancer Program 790 Commissioners Road East Recruiting
London, Ontario, Canada, N6A 4L6
Contact: Laura Meraw, RN    (519) 685-8500 ext 57135    laura.meraw@lhsc.on.ca   
Contact: Maisam Abouzeenni, CRC    (519) 685-8500 ext 56840    maisam.abouzeenni@lhsc.on.ca   
Principal Investigator: Leonard Minuk, MD         
The Ottawa Hospital Recruiting
Ottawa, Ontario, Canada, K1H 8L6
Contact: Lynne Cullen, RN    613-737-8899 ext 79376    lycullen@ohri.ca   
Contact: Holly Carr, CRC    613-737-8899 ext 73301    hcarr@toh.on.ca   
Principal Investigator: Jason Tay, MD         
Princess Margaret Cancer Centre Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Jesus G. Piza Rodriguez, MD, CCRP    416-946-4627    giovanni.piza@uhnresearch.ca   
Contact: Mariela Pantoja, PhD, CCRP    416-946-4501 ext 3655    mariela.pantoja@uhnresearch.ca   
Principal Investigator: Donna E. Reece, MD         
Sub-Investigator: Christine Chen, MD         
Sub-Investigator: Vishal Kukreti, MD         
Sub-Investigator: Suzanne Trudel, MD         
Sub-Investigator: Rodger Tiedemann, MD         
Canada, Quebec
Royal Victoria Hospital, 87 Pine Avenue West, # E-3.48 Recruiting
Montreal, Quebec, Canada, H3A 1A1
Contact: Simonetta Mulatero, CRA    (514) 934-1934 ext 35391    simonetta.mulatero@mcgill.ca   
Contact: Barbara Adamska, RN    (514) 934-1934 ext 35033    barbara.adamska@muhc.mcgill.ca   
Principal Investigator: Michael Sebag, MD         
Hôpital Maisonneuve-Rosemont, 5415, boul. de l'Assomption Recruiting
Montreal, Quebec, Canada, H1T 2M4
Contact: Nathalie Lachapelle, RN    514-252-3400 ext 4471    nlachapelle.hmr@ssss.gouv.qc.ca   
Principal Investigator: Jean Roy, MD         
Canada, Saskatchewan
Saskatoon Cancer Centre 20 Campus Drive Recruiting
Saskatoon, Saskatchewan, Canada, S7N 4H4
Contact: Anne Westad, RN    306 655-0641    anne.westad@saskcancer.ca   
Contact: Sarah Salewich, RN    306 655-2422    sarah.salewich@saskcancer.ca   
Principal Investigator: Julie Stakiw, MD         
Sponsors and Collaborators
University Health Network, Toronto
Princess Margaret Hospital, Canada
Otsuka Pharmaceutical Development & Commercialization, Inc.
Celgene Corporation
Investigators
Principal Investigator: Donna E Reece, MD University Health Network-Princess Margaret Hospital
  More Information

No publications provided

Responsible Party: University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT01702831     History of Changes
Other Study ID Numbers: MCRN 001
Study First Received: August 29, 2012
Last Updated: May 16, 2014
Health Authority: Canada: Health Canada

Keywords provided by University Health Network, Toronto:
Newly Diagnosed multiple myeloma

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
Lenalidomide
Thalidomide
Melphalan
Busulfan
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Leprostatic Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on September 18, 2014