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

NCT01702831 | Completed Phase 2 DMC

• 1 other identifier: MCRN 001
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 10

Brief Summary

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.

Conditions

Multiple Myeloma

Keywords

Newly Diagnosed multiple myeloma

Outcome Measures

Primary Outcomes (1)

• • Minimal Residual Disease (MRD) negativity at day 100 post ASCT

  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.

  day 100 post ASCT

Secondary Outcomes (8)

• • To determine the pattern, positivity (in terms of percentages) or negativity of MRD analysis during lenalidomide maintenance.

  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.

• • To determine the response rate using conventional immunoglobulin and monoclonal protein-based markers at day 100 post ASCT and best response using lenalidomide maintenance.

  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.

• • To determine the effectiveness of using the HevyLite Chain assay to assess anti-tumour response at day 100 post ASCT and during lenalidomide maintenance

  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.

• • To determine the toxicity of busulfan and melphalan when used as a high-dose conditioning therapy for ASCT.

  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.

• • To determine the toxicity of lenalidomide maintenance post busulfan and melphalan conditioning ASCT.

  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.

Study Arms (1)

BuMel + lenalidomide Maintenance

EXPERIMENTAL

I.V. Busulfan + I.V. Melphalan for conditioning prior ASCT, followed by Lenalidomide maintenance at day 100 after ASCT.

Drug: Busulfan; Drug: Melphalan; Drug: Lenalidomide

Interventions

Busulfan DRUG

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.

Also known as: Busulfex

BuMel + lenalidomide Maintenance

Melphalan DRUG

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"

Also known as: Alkeran

BuMel + lenalidomide Maintenance

Lenalidomide DRUG

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.

Also known as: Revlimid

BuMel + lenalidomide Maintenance

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 to 75 years, inclusive.
• Study participants must have a diagnosis of symptomatic multiple myeloma requiring systemic therapy and are eligible for the planned ASCT.
• Untreated bone marrow sample was shipped to Princess Margaret Hospital for MRD assay.
• Must have been treated with a velcade-based induction regimen. No limit to the number of cycles of induction.
• Study participants in whom the minimum stem cell dose of 2.0 x 106 cluster of differentiation (CD)34+ cells/kg has been collected.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
• Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test in all females of child-bearing potential (FOCBP).
• 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.

You may not qualify if:

• Myeloma progression at any time since starting initial induction therapy for multiple myeloma. Changes to or additions to the existing induction therapy are allowed as long as disease progression has not been confirmed.
• Prior treatment history of ASCT for any medical reason.
• Prior treatment history of high-dose chemotherapy with stem cell rescue for any medical reason, not limited to myeloma treatment.
• Prior treatment with busulfan or gemtuzumab ozogamicin for any reason.
• Systemic amyloidosis.
• 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.
• Uncontrolled arrhythmia or symptomatic cardiac disease at the time of screening.
• 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.
• Aspartate transaminase (AST)/alanine transaminase (ALT) ≥ 3 x the upper limit of normal (ULN).
• 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.
• Hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time as International Normalized Ratio (INR) ≥ 2.0 at the time of screening.
• 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.
• Prior total body irradiation therapy, or radiation therapy directly applied to the liver.
• 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.
• 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.

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Princess Margaret Hospital, Canada: collaborator
• Otsuka Pharmaceutical Development & Commercialization, Inc.: collaborator
• Celgene Corporation: collaborator

Study Sites (10)

Cross Cancer Institute 11560 University Ave

Edmonton, Alberta, T6G-1Z2, Canada

Location

Vancouver General Hospital, Centennial Pavilion, 6th Floor

Vancouver, British Columbia, V5Z 1M9, Canada

Location

Saint John Regional Hospital, 5DN Research Department, 400 University Ave

Saint John, New Brunswick, E2L 4L2, Canada

Location

Queen Elizabeth II Health Sciences Centre.

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

London Regional Cancer Program 790 Commissioners Road East

London, Ontario, N6A 4L6, Canada

Location

The Ottawa Hospital

Ottawa, Ontario, K1H 8L6, Canada

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

Hôpital Maisonneuve-Rosemont, 5415, boul. de l'Assomption

Montreal, Quebec, H1T 2M4, Canada

Location

Royal Victoria Hospital, MUHC Glen Site, Cedars Cancer Centre

Montreal, Quebec, H4A 3J1, Canada

Location

Saskatoon Cancer Centre 20 Campus Drive

Saskatoon, Saskatchewan, S7N 4H4, Canada

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Busulfan; Melphalan; Lenalidomide

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Donna E Reece, MD

  University Health Network-Princess Margaret Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 29, 2012
• First Posted: October 8, 2012
• Study Start: October 1, 2013
• Primary Completion: July 31, 2022
• Study Completion: July 31, 2022
• Last Updated: September 21, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR
• Time Frame: Current Study Protocol Amendment # 4 (v. date February 13, 21018), ICF(s), interim CSR have been submitted to the DSMB since the activation of this trial. DSMB meetings occur every 6 months. DSMB letters are provided to participating sites every 6 months after the DSMB meetings have occurred. IPD for correlative studies is provided ad-hoc on individual request for data analysis (i.e. submission of abstracts to conferences).
• Access Criteria: No additional information will be shared

Locations

CA (10)