High-Dose Gemcitabine, Busulfan and Melphalan With Hematopoietic-Cell Support for Patients With Poor-Risk Myeloma

Sponsor
M.D. Anderson Cancer Center (Other)
Overall Status
Completed
CT.gov ID
NCT01237951
Collaborator
(none)
75
Enrollment
1
Location
1
Arm
82.4
Actual Duration (Months)
0.9
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn if the combination of gemcitabine, busulfan, and melphalan, when given before a stem cell transplant, can help to control refractory myeloma. The safety of this study treatment will also be studied.

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

Study Drugs:

Busulfan and melphalan are designed to bind to the DNA (genetic material) of cells, which may cause cancer cells to die. They are commonly used in stem cell transplantation.

Gemcitabine is designed to disrupt the growth of cancer cells, which may cause cancer cells to die. It may help to increase the effect of busulfan and melphalan on cancer cells by not allowing these cells to repair the DNA damage caused by busulfan or melphalan.

Busulfan Test Dose:

You will receive a test dose of busulfan by vein over about 60 minutes. This low-level test dose of busulfan is to check how the level of busulfan in your blood levels changes over time. This information will be used to decide the next dose needed to reach the target blood level that matches your body size. You will most likely receive this as an outpatient during the week before you are admitted to the hospital. If it cannot be given as an outpatient, you will be admitted to the hospital on Day -11 (11 days before your stem cells are returned to your body) and the test dose will be given on Day -10.

About 11 samples of blood (about 1 teaspoon each time) will be drawn for pharmacokinetic (PK) testing. PK testing measures the amount of study drug in the body at different time points and will help the study doctor determine what your dose of busulfan should be on study. These blood samples will be drawn at various timepoints before you receive busulfan and over about the next 11 hours. The blood samples will be repeated again on the first day of high-dose busulfan treatment Day -8. A temporary heparin lock line will be placed in your vein to lower the number of needle sticks needed for these draws. If it is not possible for the PK tests to be performed, you will receive the standard dose of busulfan.

If you receive the busulfan test dose as an outpatient:

On Days -12 (12 days before your stem cells are returned to your body) through Day -10, you will receive palifermin by vein over about 30 seconds to help decrease the risk of side effects in the mouth and throat.

You will be admitted on Day -9 and will receive fluids by vein to hydrate you. You will swish the liquids caphosol and glutamine in your mouth 4 times a day, for about 2 minutes each time. You will swish these liquids every day until you leave the hospital. These drugs are also used to help decrease the risk of side effects in the mouth and throat.

On Days -8 through -5, you will receive busulfan by vein over about 3 hours.

On Days -8 and -3, you will receive gemcitabine by vein over about 3 hours.

On Day -4, you will not receive any drugs.

If you receive the busulfan test dose as an inpatient:

On Days -13 through Day -11, you will receive palifermin by vein over about 30 seconds each day to help decrease the risk of side effects in the mouth and throat.

You will be admitted on Day -11 and will receive fluids by vein to hydrate you. You will swish the liquids caphosol and glutamine in your mouth 4 times a day, for about 2 minutes each time. You will swish these liquids every day until you leave the hospital. These drugs are also used to help decrease the risk of side effects in the mouth and throat.

On Day -10, you will receive the busulfan test dose by vein over 45 minutes.

On Day -9, you will not receive any drugs.

On Days -8 and -3, you will receive gemcitabine by vein over about 3 hours on both days.

On Days -8 through -5, you will receive busulfan by vein over about 3 hours each day.

Study Drug Administration (for all patients):

On Days -9 through -2, you will receive dexamethasone by vein over about 15 minutes to help decrease the risk of the possible side effects of the study drugs.

On Days -3 and -2, you will receive melphalan by vein over about 30 minutes on both days.

On Day -1, you will not receive any drugs.

On Day 0, your stem cells will be returned to your body by vein over 30-60 minutes.

On Days 0 through 2, you will receive palifermin by vein over about 30 seconds each day.

Beginning on Day 5, you will receive filgrastim (a drug that helps with the growth of white blood cells) through a needle under your skin 1 time each day until your blood cell levels return to normal.

Study Tests:

While you are in the hospital, you will be checked for any side effects as part of your standard of care. Blood (about 2 teaspoons) will be drawn every day to check for side effects.

As part of standard care, you will remain in the hospital for about 3-4 weeks after the transplant. After you are released from the hospital, you must remain in the Houston area to be monitored for infections and other transplant side effects until about Day 30. During this time, you will return to the clinic 1 time each week and the following tests and procedures will be performed:

  • You will be asked about how you are feeling and about any side effects you may be having.

  • Blood (about 2 teaspoons) will be drawn for routine tests.

  • You will have a lung function test about 30-100 days after the transplant.

Length of Study:

You will be followed as part as the study for at least 2 years. You may be taken off study early if the disease gets worse or you experience any intolerable side effects.

At each follow-up visit the following tests and procedures will be performed:
  • Your medical history will be recorded.

  • You will have a physical exam.

  • Blood (about 2 teaspoons) and urine will be collected for routine tests.

  • If your doctor thinks it is needed, you will have a bone marrow biopsy to check the status of the disease.

  • Bone survey: Only once a year.

You must talk to the study doctor if you want to leave the study early. It may be life-threatening to leave the study after you have begun to receive the study drugs but before you receive the stem cells.

This is an investigational study. Busulfan, gemcitabine, and melphalan are all FDA approved and commercially available for the treatment of lymphoma, myeloma, and several other tumors. The use of these study drugs together and the use of gemcitabine at the dose level used in this study is investigational.

Up to 75 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

Study Type:
Interventional
Actual Enrollment :
75 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
High-dose Gemcitabine, Busulfan and Melphalan With Autologous Hematopoietic-Cell Support for Patients With Poor-Risk Myeloma
Actual Study Start Date :
Nov 8, 2010
Actual Primary Completion Date :
Sep 20, 2017
Actual Study Completion Date :
Sep 20, 2017

Arms and Interventions

ArmIntervention/Treatment
Experimental: GemBuMel

Gemcitabine 1875 mg/m^2 IV (75 mg/ m2 bolus followed by 1800 mg/m^2 over 3 hours) on Day -8 and Day -3 as an outpatient or inpatient. Busulfan 32 mg/m2 test dose with PKs as outpatient before Day -12, or as an inpatient on Day -10. Busulfan area under curve (AUC) 4,000 by vein on Days -8 to -5 as an outpatient or inpatient. Melphalan 60 mg/m^2 IV on Days -3 and -2 over 30 minutes on both days as an outpatient or inpatient. Palifermin 60 micrograms/kg infused as an IVP (by vein) over 15-30 seconds Days -12 to -10 and Days 0 to +2 as an outpatient. Palifermin 60 micrograms/kg by vein on Days -13 to -11 and on Days 0, +1 and +2 as in inpatient. Dexamethasone 8 mg IV twice a day by vein over 15 minutes Days -9 through -2 as an outpatient or inpatient. G-CSF 5 mcg/kg/day subcutaneously beginning on Day +5 and continuing until neutrophil recovery is documented. Stem Cell Transplant: On Day 0, stem cells returned to body by vein over 30-60 minutes.

Drug: Palifermin
60 micrograms/kg infused as an IVP (by vein) over 15-30 seconds Days -12 to -10 and Days 0 to +2 as an outpatient. 60 micrograms/kg by vein on Days -13 to -11 and on Days 0, +1 and +2 as in inpatient.
Other Names:
  • kepivance
  • Drug: Dexamethasone
    8 mg IV twice a day by vein over 15 minutes Days -9 through -2 as an outpatient or inpatient.
    Other Names:
  • decadron
  • Drug: Gemcitabine
    1875 mg/m^2 IV (75 mg/ m2 bolus followed by 1800 mg/m^2 over 3 hours) on Day -8 and Day -3 as an outpatient or inpatient.
    Other Names:
  • Gemcitabine Hydrochloride
  • Gemzar
  • Drug: Busulfan
    32 mg/m2 test dose with PKs as outpatient before Day -12, or as an inpatient on Day -10. Busulfan AUC 4,000 by vein on Days -8 to -5 as an outpatient or inpatient.
    Other Names:
  • myleran
  • busulfex
  • Drug: Melphalan
    60 mg/m^2 IV on Days -3 and -2 over 30 minutes on both days as an outpatient or inpatient.
    Other Names:
  • Alkeran
  • Procedure: Stem Cell Transplant
    On Day 0, stem cells returned to body by vein over 30-60 minutes.
    Other Names:
  • SCT
  • ASCT
  • Drug: G-CSF
    5 mcg/kg/day subcutaneously beginning on Day +5 and continuing until neutrophil recovery is documented.
    Other Names:
  • Filgrastim
  • Neupogen
  • Outcome Measures

    Primary Outcome Measures

    1. Participants Who Had Measurable Disease at Time of Transplant and Achieved a Stringent Complete Remission [100 days post-transplant]

      Stringent complete remission was defined as negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, 5% or fewer plasma cells in bone marrow, normal free light chain ratio, and the absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.

    Secondary Outcome Measures

    1. Progression-free Survival (PFS) [From date of transplant until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years.]

      Number of participants remain free of progression or death after ASCT

    2. Overall Survival [From date of transplant until the date of death from any cause, assessed up to 2 years]

      Number of participants from ASCT to death or last contact

    3. Percent of Participants Dying From Treatment-Related Complications [From date of transplant until the date of death from treatment-related complications, assessed up to 2 years]

      Participants who died from treatment-related complications from the time of ASCT.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Age 18 to 70 years.

    2. Patients with myeloma treated with first-line therapy including lenalidomide, bortezomib or thalidomide, and one or more of the following: 2.1) M paraprotein greater than 1 g/dL at HDC. 2.2) Less than partial response to first-line therapy. 2.3) Relapse after first-line therapy. 2.4) Relapse after a prior autologous stem-cell transplant.

    3. Adequate renal function, as defined by serum creatinine </=1.8 mg/dL and/or estimated serum creatinine clearance >/=50 ml/min

    4. Adequate hepatic function, as defined by serum glutamate oxaloacetate transaminase (SGOT) and/or serum glutamate pyruvate transaminase (SGPT) </=3 x upper limit of normal; serum bilirubin and alkaline phosphatase </=2 x upper limit of normal, unless proven to be due to disease involvement.

    5. Adequate pulmonary function with forced expiratory volume at one second (FEV1), forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (DLCO) >/=50% of expected corrected for hemoglobin and/or volume.

    6. Adequate cardiac function with left ventricular ejection fraction >/=40%. No uncontrolled arrhythmias or symptomatic cardiac disease.

    7. Zubrod performance status <2.

    8. Negative Beta human chorionic gonadotropin (HCG) text in a woman with child-bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization

    Exclusion Criteria:
    1. Patients with grade >/= 3 non-hematologic toxicity from previous therapy that has not resolved to </= grade 1.

    2. Patients with prior whole brain irradiation

    3. Patients with active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA

    /=10,000 copies/mL, or >/= 2,000 IU/mL).

    1. Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology.

    2. Active infection requiring parenteral antibiotics.

    3. HIV infection, unless the patient is receiving effective antiretroviral therapy with undetectable viral load and normal cluster of differentiation 4 (CD4) counts

    4. Patients having received radiation therapy to head and neck (excluding eyes), and internal organs of chest, abdomen or pelvis in the month prior to enrollment.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1University of Texas MD Anderson Cancer CenterHoustonTexasUnited States77030

    Sponsors and Collaborators

    • M.D. Anderson Cancer Center

    Investigators

    • Study Chair: Yago Nieto, MD, PhD, 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:
    NCT01237951
    Other Study ID Numbers:
    • 2010-0506
    • NCI-2012-01906
    First Posted:
    Nov 10, 2010
    Last Update Posted:
    May 5, 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 DetailsParticipants were enrolled at the University of Texas MD Anderson Cancer Center. Out of 75, 1 participant died before starting the treatment.
    Pre-assignment Detail
    Arm/Group TitleGemcitabine/Busulfan/Melphalan
    Arm/Group DescriptionPatients ages 18-70 with primary refractory or relapsed myeloma, candidates for an autologous SCT (ASCT) who had previously received treatment with bortezomib, an immunomodulatory drug, or both, or who were receiving a salvage ASCT.
    Period Title: Overall Study
    STARTED75
    COMPLETED74
    NOT COMPLETED1

    Baseline Characteristics

    Arm/Group TitleGemcitabine/Busulfan/Melphalan
    Arm/Group DescriptionPatients ages 18-70 with primary refractory or relapsed myeloma, candidates for an autologous SCT (ASCT) who had previously received treatment with bortezomib, an immunomodulatory drug, or both, or who were receiving a salvage ASCT.
    Overall Participants74
    Age (years) [Median (Standard Deviation) ]
    Median (Standard Deviation) [years]
    58.5
    (5.5)
    Sex: Female, Male (Count of Participants)
    Female
    17
    23%
    Male
    57
    77%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    3
    4.1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    16
    21.6%
    White
    55
    74.3%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    74
    100%
    Overall study group (participants) [Number]
    1st SCT/salvage SCT
    13
    17.6%
    Poor-risk cytogenetics
    6
    8.1%
    Extramedullary disease
    1
    1.4%
    Double refractory (IMiDs + proteasome inhibitors)
    11
    14.9%
    Disease Status: Primary refractory
    4
    5.4%
    Disease Status: Refractory relapse
    11
    14.9%
    Disease Status: Sensitive relapse
    4
    5.4%
    Response at ASCT: Response
    8
    10.8%
    Response at ASCT: Refractory
    11
    14.9%
    No. prior lines of treatment
    10
    13.5%
    No. prior lines of treatment > 2
    9
    12.2%
    Post-ASCT maintenance
    16
    21.6%

    Outcome Measures

    1. Primary Outcome
    TitleParticipants Who Had Measurable Disease at Time of Transplant and Achieved a Stringent Complete Remission
    DescriptionStringent complete remission was defined as negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, 5% or fewer plasma cells in bone marrow, normal free light chain ratio, and the absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.
    Time Frame100 days post-transplant

    Outcome Measure Data

    Analysis Population Description
    Only 65 participants had measurable disease at the time of ASCT.
    Arm/Group TitleGemcitabine/Busulfan/Melphalan
    Arm/Group DescriptionPatients with refractory or relapsed myeloma received high-dose GemBuMel with ASCT
    Measure Participants65
    Count of Participants [Participants]
    16
    21.6%
    2. Secondary Outcome
    TitleProgression-free Survival (PFS)
    DescriptionNumber of participants remain free of progression or death after ASCT
    Time FrameFrom date of transplant until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleGemcitabine/Busulfan/Melphalan
    Arm/Group DescriptionPatients with refractory or relapsed myeloma received high-dose GemBuMel with ASCT
    Measure Participants74
    Count of Participants [Participants]
    31
    41.9%
    3. Secondary Outcome
    TitleOverall Survival
    DescriptionNumber of participants from ASCT to death or last contact
    Time FrameFrom date of transplant until the date of death from any cause, assessed up to 2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleGemcitabine/Busulfan/Melphalan
    Arm/Group DescriptionPatients with refractory or relapsed myeloma received high-dose GemBuMel with ASCT
    Measure Participants74
    Count of Participants [Participants]
    49
    66.2%
    4. Secondary Outcome
    TitlePercent of Participants Dying From Treatment-Related Complications
    DescriptionParticipants who died from treatment-related complications from the time of ASCT.
    Time FrameFrom date of transplant until the date of death from treatment-related complications, assessed up to 2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleGemcitabine/Busulfan/Melphalan
    Arm/Group DescriptionPatients with refractory or relapsed myeloma received high-dose GemBuMel with ASCT
    Measure Participants74
    Count of Participants [Participants]
    4
    5.4%

    Adverse Events

    Time FrameUp to 2 years
    Adverse Event Reporting Description All-Cause Mortality was monitored in for all enrolled 75 participants ( 1 participant died before receiving treatment and 4 while on study) and 74 participants with Serious and Other Adverse Events.
    Arm/Group TitleGemcitabine/Busulfan/Melphalan
    Arm/Group DescriptionParticipants with refractory or relapsed myeloma received high-dose GemBuMel with ASCT.
    All Cause Mortality
    Gemcitabine/Busulfan/Melphalan
    Affected / at Risk (%)# Events
    Total5/75 (6.7%)
    Serious Adverse Events
    Gemcitabine/Busulfan/Melphalan
    Affected / at Risk (%)# Events
    Total31/74 (41.9%)
    Cardiac disorders
    Cardiac2/74 (2.7%)
    Gastrointestinal disorders
    Mucositis13/74 (17.6%)
    Diarrhea2/74 (2.7%)
    Hepatobiliary disorders
    Hyperbilirubinemia9/74 (12.2%)
    Infections and infestations
    Infection5/74 (6.8%)
    Skin and subcutaneous tissue disorders
    Dermatitis5/74 (6.8%)
    Other (Not Including Serious) Adverse Events
    Gemcitabine/Busulfan/Melphalan
    Affected / at Risk (%)# Events
    Total71/74 (95.9%)
    Cardiac disorders
    Cardiac54/74 (73%)
    Gastrointestinal disorders
    Mucositis55/74 (74.3%)
    Diarrhea13/74 (17.6%)
    Hepatobiliary disorders
    Hyperbilirubinemia9/74 (12.2%)
    Immune system disorders
    Infection71/74 (95.9%)
    Skin and subcutaneous tissue disorders
    Dermatitis34/74 (45.9%)
    Hand-foot syndrome1/74 (1.4%)

    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. Nieto, Yago, M.D./Stem Cell Transplantation
    OrganizationUT MD Anderson Cancer Center
    Phone713-792-2466
    Emailynieto@mdanderson.org
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT01237951
    Other Study ID Numbers:
    • 2010-0506
    • NCI-2012-01906
    First Posted:
    Nov 10, 2010
    Last Update Posted:
    May 5, 2020
    Last Verified:
    Apr 1, 2020