A Randomized Trial to Compare Busulfan + Melphalan 140 mg/m2 With Melphalan 200 mg/m2 as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Sponsor
M.D. Anderson Cancer Center (Other)
Overall Status
Completed
CT.gov ID
NCT01413178
Collaborator
Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
205
Enrollment
1
Location
2
Arms
89.3
Actual Duration (Months)
2.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to compare Busulfex (busulfan) with or without Alkeran (melphalan) to learn which study therapy may be better at helping to control MM in patients who will receive an autologous stem cell transplant. The safety of this combination therapy will also be studied.

Melphalan and busulfan are designed to damage the DNA (genetic material) of cells, which may cause cancer cells to die.

Condition or DiseaseIntervention/TreatmentPhase
Phase 3

Detailed Description

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups.

  • Group 1 will receive melphalan and busulfan.

  • Group 2 will receive melphalan.

Both groups will have a stem cell transplant.

Study Drug Administration:

If you are in Group 1, you will first receive an additional low-level "test" dose of busulfan given by vein to check how your blood levels change over time. This information will be used to decide the next dose that is needed to reach a target blood level of busulfan. Blood (about 1 teaspoon each time) will be drawn up to 11 times during the next 11 hours after the test dose and the first high-dose busulfan treatment.

A heparin lock line will be placed in a vein to lower the number of needle sticks needed for these draws.

This test dose of busulfan can be given as an outpatient before you are admitted to the hospital, or you will be admitted on Day -10 (10 days before your transplant) and will receive the test dose on Day -9. If it is not possible for these blood level tests to be performed for technical or scheduling reasons, you will receive the standard, fixed (unchanging) dose of busulfan.

Eight (8) or 10 days before the transplant, you will be admitted to the hospital and given hydration fluids by vein.

On Days -7, -6, -5, and -4, you will receive busulfan by vein over 3 hours. You will receive melphalan on Days -2 and -1 by vein over 30 minutes. You will receive the stem cell transplant through the CVC on Day 0.

If you are in Group 2, you may be admitted to the hospital 3 days before the transplant. You will receive hydration fluids by vein. Two (2) days before the transplant, you will receive melphalan by vein over 30 minutes. You will not receive melphalan the day before the transplant.

Stem Cell Transplant:

The day that you receive the stem cell transplant is called Day 0. The stem cells will be given by vein through the CVC. The cells will travel to your bone marrow where they are designed to start making healthy, new blood cells after several weeks. You will sign a separate consent for the collection of your stem cells.

Beginning 5 days after the transplant, you will receive filgrastim (G-CSF) through a needle under your skin 1 time each day until your blood cell levels return to normal. Filgrastim is designed to help with the growth of white blood cells.

You will be in the hospital after the transplant for about 2-4 weeks.

Questionnaire:

You will be asked to complete a quality-of-life questionnaire before starting the study drugs and then once a week during Weeks 1, 2, and 4 after the stem cell transplant. The questionnaire will take about 15 minutes to complete.

Follow-Up Visits:

About 3 months after the transplant, you will have a bone marrow aspiration and biopsy to check the status of the disease. To collect a bone marrow aspiration and biopsy, an area of the hip is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle.

Every 3 months during the first year after the transplant, blood (about 1-2 tablespoons) will be drawn to check your immune response and status of the disease.

About 1 year after the transplant, you will have a bone scan if the doctor thinks it is needed.

Length of Study:

One (1) year after the transplant, your participation in this study will be over.

If intolerable side effects from the chemotherapy occur or there is sign of disease after the transplant, you will be taken off study. If you have intolerable side effects after you receive chemotherapy, then you will still have the transplant. If you are taken off study early, you still may need to return for routine post-transplant follow-up visits, if your transplant doctor decides it is needed.

This is an investigational study. Busulfan and melphalan are commercially available and FDA approved for the treatment of myeloma. The use of melphalan alone before an autologous stem cell transplant is considered standard of care. Using busulfan with melphalan is investigational.

Up to 205 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

Study Type:
Interventional
Actual Enrollment :
205 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized Trial to Compare Busulfan + Melphalan 140 mg/m2 With Melphalan 200 mg/m2 as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma
Actual Study Start Date :
Sep 30, 2011
Actual Primary Completion Date :
Mar 10, 2019
Actual Study Completion Date :
Mar 10, 2019

Arms and Interventions

ArmIntervention/Treatment
Experimental: Busulfan + Melphalan

Busulfan test dose (32 mg/m^2) on day -9 then 130 mg/m^2 intravenous (IV) Days -7, -6, -5, and -4 + Melphalan 70 mg/m2 IV on Days -2 and -1. Stem Cell Transplant (SCT) Day 0.

Drug: Busulfan
Test dose (32 mg/m^2) on day -9 then 130 mg/m^2 by vein or adjusted dose on Days -7, -6, -5, and -4.
Other Names:
  • Busulfex
  • Myleran
  • Drug: Melphalan
    70 mg/m2 by vein over 30 minutes minutes on Days -2 and -1.
    Other Names:
  • Alkeran
  • Other: Questionnaire
    Quality of Life (QOL) questionnaire before starting the study drugs and then once every 4 weeks after the stem cell transplant, taking about 15 minutes to complete.
    Other Names:
  • Survey
  • Drug: G-CSF
    Approximately 5 mcg/kg/day subcutaneously beginning on Day +5.
    Other Names:
  • Filgrastim
  • NeupogenTM
  • Procedure: Stem cell transplant
    Stem cell infusion on Day 0.
    Other Names:
  • ABMT
  • autologous bone marrow transplantation
  • Peripheral Blood Progenitor Cells
  • PBPCs
  • Experimental: Melphalan

    High-dose Melphalan 200 mg/m2/day IV over 30 minutes on day -2. SCT Day 0.

    Other: Questionnaire
    Quality of Life (QOL) questionnaire before starting the study drugs and then once every 4 weeks after the stem cell transplant, taking about 15 minutes to complete.
    Other Names:
  • Survey
  • Drug: G-CSF
    Approximately 5 mcg/kg/day subcutaneously beginning on Day +5.
    Other Names:
  • Filgrastim
  • NeupogenTM
  • Drug: High Dose Melphalan
    200 mg/m2 by vein over 30 minutes on Day -2.
    Other Names:
  • Alkeran
  • Procedure: Stem cell transplant
    Stem cell infusion on Day 0.
    Other Names:
  • ABMT
  • autologous bone marrow transplantation
  • Peripheral Blood Progenitor Cells
  • PBPCs
  • Outcome Measures

    Primary Outcome Measures

    1. Progression-Free Survival (PFS) [3 years after transplant]

      Participants that are still alive and without Multiple Myeloma 3 years after Stem cell Transplantation.

    Secondary Outcome Measures

    1. Number of Participants With Complete Response (CR) [Evaluated 90 days from transplant.]

      Complete response (CR), evaluated 90 days from transplant, defined as (i) negative immunofixation of the multiple myeloma (MM) protein in urine and serum, (ii) disappearance of any soft tissue plasmacytomas, and (iii) less than 5% plasma MM cells in the bone marrow. International Myeloma Working Group uniform response criteria.

    2. Treatment-Related Mortality (TRM) Between 2 Arms. [100 days post treatment]

    3. Number of Participants That Had Grade 3-4 Toxicities. [At day 90 post SCT (Stem Cell Transplantation)]

    4. Overall Survival (OS) [From time of ASCT to 3 years]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Patients with multiple myeloma in complete remission (CR), partial remission (PR), or very good partial remission (VGPR), or symptomatic stable disease (no evidence of progression) including patients with light chain MM detected in the serum by free light chain assay.

    2. Patients with non-secretory multiple myeloma [absence of a monoclonal protein (M protein) in serum as measured by electrophoresis (SPEP) and immunofixation (SIFE) and the absence of Bence Jones protein in the urine (UPEP) defined by use of conventional electrophoresis and immunofixation (UIFE) techniques] but with measurable disease on imaging studies like MRI, CT scan or PET scan.

    3. Who have received at least two cycles of initial systemic therapy and are within 2 to 12 months of the first dose. Mobilization therapy is not considered initial therapy.

    4. 70 years of age or younger.

    5. Karnofsky performance score 70% or higher.

    6. Cardiac function: left ventricular ejection fraction at rest > 40% within 3 months of registration.

    7. Hepatic function: bilirubin < 2x the upper limit of normal and ALT and AST < 2.5x the upper limit of normal.

    8. Renal function: creatinine clearance of >/= 40 mL/min, estimated or calculated.

    9. Pulmonary function: DLCO, FEV1, FVC >/= 50% of predicted value (corrected for hemoglobin) within 3 months of registration

    10. Signed informed consent form.

    Exclusion Criteria:
    1. Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms).

    2. Patients seropositive for the human immunodeficiency virus (HIV).

    3. Patients with history of myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.

    4. Patients participating in an investigational new drug protocol within 14 days before enrollment.

    5. Female patients who are pregnant (positive b-HCG) or breastfeeding.

    6. Prior stem cell transplantation allogeneic or autologous.

    7. Prior organ transplant requiring immunosuppressive therapy.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1University of Texas MD Anderson Cancer CenterHoustonTexasUnited States77030

    Sponsors and Collaborators

    • M.D. Anderson Cancer Center
    • Otsuka Pharmaceutical Development & Commercialization, Inc.

    Investigators

    • Principal Investigator: Muzaffar H. Qazilbash, MD, M.D. Anderson Cancer Center

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT01413178
    Other Study ID Numbers:
    • 2010-0071
    • NCI-2011-02760
    First Posted:
    Aug 10, 2011
    Last Update Posted:
    Apr 21, 2020
    Last Verified:
    Apr 1, 2020
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by M.D. Anderson Cancer Center
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment DetailsAll participants were registered in MD Anderson Cancer.
    Pre-assignment Detail
    Arm/Group TitleBusulfan + MelphalanMelphalan
    Arm/Group DescriptionBusulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplantHigh-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
    Period Title: Overall Study
    STARTED105100
    COMPLETED10498
    NOT COMPLETED12

    Baseline Characteristics

    Arm/Group TitleBusulfan + MelphalanMelphalanTotal
    Arm/Group DescriptionBusulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplant.High-dose Melphalan 200 mg/m2/day followed by a stem cell transplantTotal of all reporting groups
    Overall Participants10498202
    Age (years) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [years]
    58.9
    59.5
    59.2
    Sex: Female, Male (Count of Participants)
    Female
    43
    41.3%
    43
    43.9%
    86
    42.6%
    Male
    61
    58.7%
    55
    56.1%
    116
    57.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    5
    4.8%
    1
    1%
    6
    3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    15
    14.4%
    24
    24.5%
    39
    19.3%
    White
    75
    72.1%
    67
    68.4%
    142
    70.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    9
    8.7%
    6
    6.1%
    15
    7.4%
    Region of Enrollment (participants) [Number]
    United States
    104
    100%
    98
    100%
    202
    100%

    Outcome Measures

    1. Primary Outcome
    TitleProgression-Free Survival (PFS)
    DescriptionParticipants that are still alive and without Multiple Myeloma 3 years after Stem cell Transplantation.
    Time Frame3 years after transplant

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleBusulfan + MelphalanMelphalan
    Arm/Group DescriptionBusulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplantHigh-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
    Measure Participants10498
    Count of Participants [Participants]
    72
    69.2%
    50
    51%
    2. Secondary Outcome
    TitleNumber of Participants With Complete Response (CR)
    DescriptionComplete response (CR), evaluated 90 days from transplant, defined as (i) negative immunofixation of the multiple myeloma (MM) protein in urine and serum, (ii) disappearance of any soft tissue plasmacytomas, and (iii) less than 5% plasma MM cells in the bone marrow. International Myeloma Working Group uniform response criteria.
    Time FrameEvaluated 90 days from transplant.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleBusulfan + MelphalanMelphalan
    Arm/Group DescriptionBusulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplantHigh-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
    Measure Participants10498
    Count of Participants [Participants]
    12
    11.5%
    15
    15.3%
    3. Secondary Outcome
    TitleTreatment-Related Mortality (TRM) Between 2 Arms.
    Description
    Time Frame100 days post treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleBusulfan + MelphalanMelphalan
    Arm/Group DescriptionBusulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplantHigh-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
    Measure Participants10498
    Count of Participants [Participants]
    0
    0%
    0
    0%
    4. Secondary Outcome
    TitleNumber of Participants That Had Grade 3-4 Toxicities.
    Description
    Time FrameAt day 90 post SCT (Stem Cell Transplantation)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleBusulfan + MelphalanMelphalan
    Arm/Group DescriptionBusulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplantHigh-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
    Measure Participants10498
    Grade 3 - Diarrhea
    5
    4.8%
    4
    4.1%
    Grade 3 - Elevated ALT
    3
    2.9%
    0
    0%
    Grade 3 - Elevated Tbili
    2
    1.9%
    0
    0%
    Grade 3 - Infection
    16
    15.4%
    5
    5.1%
    Grade 3 - Mucositis
    15
    14.4%
    0
    0%
    Grade 3 - Nausea
    5
    4.8%
    2
    2%
    Grade 3 - Neuropathy
    1
    1%
    0
    0%
    Grade 3 - Neutropenic fever
    73
    70.2%
    32
    32.7%
    Grade 3 - Pneumonia
    1
    1%
    1
    1%
    Grade 3 - Tachycardia
    1
    1%
    0
    0%
    Grade 3 - Transient blindness
    1
    1%
    0
    0%
    Grade 3 - Anorexia
    1
    1%
    0
    0%
    Grade 3 - Myocardial ischemia
    1
    1%
    1
    1%
    Grade 3 - Pleural effusion
    0
    0%
    1
    1%
    Grade 3 - Rash
    0
    0%
    1
    1%
    5. Secondary Outcome
    TitleOverall Survival (OS)
    Description
    Time FrameFrom time of ASCT to 3 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleBusulfan + MelphalanMelphalan
    Arm/Group DescriptionBusulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplantHigh-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
    Measure Participants10498
    Count of Participants [Participants]
    91
    87.5%
    79
    80.6%

    Adverse Events

    Time FrameFrom the time of ASCT until 12 months.
    Adverse Event Reporting Description
    Arm/Group TitleBusulfan + MelphalanMelphalan
    Arm/Group DescriptionBusulfan with a target daily area under the curve (AUC) of 5000 with Melphalan 70 mg/m2 followed by a stem cell transplantHigh-dose Melphalan 200 mg/m2/day followed by a stem cell transplant
    All Cause Mortality
    Busulfan + MelphalanMelphalan
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total23/104 (22.1%) 21/98 (21.4%)
    Serious Adverse Events
    Busulfan + MelphalanMelphalan
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total73/104 (70.2%) 32/98 (32.7%)
    Cardiac disorders
    Myocardial ischemia1/104 (1%) 1/98 (1%)
    Tachycardia1/104 (1%) 0/98 (0%)
    Eye disorders
    Transient blindness1/104 (1%) 0/98 (0%)
    Gastrointestinal disorders
    Diarrhea5/104 (4.8%) 4/98 (4.1%)
    Mucositis15/104 (14.4%) 0/98 (0%)
    Nausea5/104 (4.8%) 2/98 (2%)
    Hepatobiliary disorders
    Elevated ALT3/104 (2.9%) 0/98 (0%)
    Elevated Tbili2/104 (1.9%) 0/98 (0%)
    Infections and infestations
    Infection16/104 (15.4%) 6/98 (6.1%)
    Neutropenic fever73/104 (70.2%) 32/98 (32.7%)
    Nervous system disorders
    Neuropathy1/104 (1%) 0/98 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pneumonia1/104 (1%) 0/98 (0%)
    Pleural effusion0/104 (0%) 1/98 (1%)
    Skin and subcutaneous tissue disorders
    Rash0/104 (0%) 1/98 (1%)
    Other (Not Including Serious) Adverse Events
    Busulfan + MelphalanMelphalan
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total101/104 (97.1%) 98/98 (100%)
    Blood and lymphatic system disorders
    Elevated creatinine3/104 (2.9%) 0/98 (0%)
    Cardiac disorders
    Arrhythmia1/104 (1%) 0/98 (0%)
    Atrial fibrillation1/104 (1%) 1/98 (1%)
    Fluid overload63/104 (60.6%) 22/98 (22.4%)
    Hypertension16/104 (15.4%) 5/98 (5.1%)
    Hypotension1/104 (1%) 0/98 (0%)
    Tachycardia4/104 (3.8%) 1/98 (1%)
    Myocardial ischemia0/104 (0%) 1/98 (1%)
    Ear and labyrinth disorders
    Tinnitus1/104 (1%) 0/98 (0%)
    Gastrointestinal disorders
    Diarrhea57/104 (54.8%) 82/98 (83.7%)
    Mucositis86/104 (82.7%) 49/98 (50%)
    Nausea99/104 (95.2%) 98/98 (100%)
    Hepatobiliary disorders
    Elevated ALT31/104 (29.8%) 1/98 (1%)
    Elevated AST1/104 (1%) 1/98 (1%)
    Elevated Tbili8/104 (7.7%) 9/98 (9.2%)
    Infections and infestations
    Fever17/104 (16.3%) 8/98 (8.2%)
    Infection18/104 (17.3%) 17/98 (17.3%)
    Neutropenic fever1/104 (1%) 33/98 (33.7%)
    Musculoskeletal and connective tissue disorders
    Weakness of extremities1/104 (1%) 0/98 (0%)
    involuntary leg movements0/104 (0%) 1/98 (1%)
    Nervous system disorders
    Dizziness1/104 (1%) 0/98 (0%)
    Headache2/104 (1.9%) 0/98 (0%)
    Neuropathy0/104 (0%) 1/98 (1%)
    Psychiatric disorders
    Anorexia0/104 (0%) 3/98 (3.1%)
    Renal and urinary disorders
    Hematuria3/104 (2.9%) 2/98 (2%)
    Reproductive system and breast disorders
    Dysuria1/104 (1%) 0/98 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pneumonia5/104 (4.8%) 4/98 (4.1%)
    Pulmonary edema2/104 (1.9%) 0/98 (0%)
    Pleural effusion0/104 (0%) 1/98 (1%)
    Shortness of breath0/104 (0%) 1/98 (1%)
    Skin and subcutaneous tissue disorders
    Chemo burns3/104 (2.9%) 0/98 (0%)
    Rash5/104 (4.8%) 4/98 (4.1%)
    Lip ulcer0/104 (0%) 1/98 (1%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleDr. Muzaffar H. Qazilbash / Stem Cell Transplantation and Cellular Therapy
    OrganizationU.T. MD Anderson Cancer Center
    Phone713-745-3219
    Emailmqazilba@mdanderson.org
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT01413178
    Other Study ID Numbers:
    • 2010-0071
    • NCI-2011-02760
    First Posted:
    Aug 10, 2011
    Last Update Posted:
    Apr 21, 2020
    Last Verified:
    Apr 1, 2020