Azacitidine After Allo Blood And Marrow Transplantation (BMT) for Chronic Myelogenous Leukemia (CML)

Sponsor
M.D. Anderson Cancer Center (Other)
Overall Status
Completed
CT.gov ID
NCT00813124
Collaborator
National Cancer Institute (NCI) (NIH), Celgene Corporation (Industry)
24
1
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69
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Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn if Vidaza (azacitidine) when given to patients with CML after an donor stem cell transplant will increase the likelihood of achieving a complete remission of CML.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Study Drug:

Azacitidine is designed to block genes in cancer cells that stop the function of the tumor-fighting genes. By blocking the "bad" genes, the tumor-fighting genes may be able to work better.

Study Drug Administration and Procedures before the Stem Cell Transplant:

If you are found to be eligible to take part in this study, you will be given chemotherapy before the transplant of donor cells. The chemotherapy is designed to kill leukemia cells and will also block your body's ability to reject the donor cells that will be given to you during the transplant. You will receive the chemotherapy on the days before the transplant. You will receive the transplant on Day 0.

This low-level test dose of busulfan is to check how fast busulfan is processed by your body and cleared from your blood. This information will help the doctor decide the dose of busulfan you will receive. You may receive the busulfan test dose as an outpatient during the week before you are admitted to the hospital or as an inpatient on Day -8 (8 days before your stem cell transplant).

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. These blood samples will be drawn at various times before you receive busulfan and over the next 11 hours. These blood draws will be repeated again on the first day of high-dose busulfan treatment (Day -5).

A heparin lock line (small IV 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 for technical or scheduling reasons, you will receive the standard fixed dose of busulfan.

On Days -5 through -2, you will receive fludarabine by vein over 1 hour, then busulfan by vein over 3 hours.

If you are going to be receiving a transplant from an unrelated donor, or if you have a donor that is mismatched, you will also receive antithymocyte globulin (ATG) by vein over 4 hours on the 3 days before the transplant. This drug is designed to further weaken your immune system to reduce the risk of rejecting of the transplant.

Stem Cell Transplant:

After the blood-forming cells are collected from the donor, they will be given to you by vein. You will be given standard drugs to help decrease the risk of side effects. You may ask the study staff for information about how the drugs are given and their risks.

Drugs to Prevent Infections:

You will receive several drugs to help the stem cell transplant work and to help decrease the risks of infections while your immune system is weak. Tacrolimus and methotrexate will be given to decrease the risk of graft-versus-host disease (GVHD), a problem that may occur if the donor's immune cells fight your body.

  • Tacrolimus will be started 2 days before the transplant and will continue for as long as your doctor thinks is necessary. This is usually 3-12 months, but may be longer if you develop GVHD. Tacrolimus is given by vein non-stop until you are able to eat. Once you can eat, it will be given by mouth.

  • Methotrexate is given by vein over about 15-30 minutes on Days 1, 3, 6, and 11.

Several drugs will also be given to decrease the risk of other infections. Some of these antibiotics are given by vein, and some are given as pills. The length of time that you will take the antibiotics will vary. Your doctor will describe this to you in more detail.

Study Drug Administration after the Stem Cell Transplant:

You will receive azacitidine as an injection under the skin once a day over 5 days in a row, starting about 5 weeks after the transplant. This may be repeated once a month for up to 4 months after the transplant. You will have about 23 days of "rest" between each cycle of treatment (a cycle is the period of 28 days). If intolerable side effects occur, treatment with azacitidine may be interrupted or stopped altogether.

Study Visits:

You will be in the hospital for about 3-4 weeks after the transplant. You will have check-ups every day until you leave the hospital. After you leave, the number of study visits will vary, depending on your condition.

You will have bone marrow aspirations collected before chemotherapy, around 1, 6, and 12 months after the transplant. To collect a bone marrow aspirate, an area of the hip bone is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle. The bone marrow samples will be used to check the status of the disease and to learn the way azacitidine works.

Blood (about 2 teaspoons each time) will be drawn to learn about patterns of a process called methylation. Methylation is a process by which the body may turn "on and off" certain genes.

Blood will be drawn at the following times:
  • At baseline.

  • Before the stem cell transplant (Day 0).

  • Six (6), 9, and 12 months after the transplant.

  • Before you receive your first dose of azacitidine (Day 1 of each cycle).

  • After you receive the last dose of azacitidine (Day 5 of each cycle).

Blood (about 8 teaspoons each time) will be drawn to learn about the body's immune system recovery, at the following times:

  • Cycle 1- Day 1

  • Cycle 1 - Day 14

  • Cycle 3 - Day 1

Length of Study:

You will remain on study for up to 1 year. You may be taken off study early if the disease gets worse or intolerable side effects occur.

This is an investigational study. Azacitidine is FDA approved and commercially available in patients with myelodysplastic syndrome. Its use in patients with CML is investigational. All other drugs used in this study are FDA approved and commercially available.

Up to 57 patients will take part in this study. All will be enrolled at MD Anderson.

Study Design

Study Type:
Interventional
Actual Enrollment :
24 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Azacitidine Maintenance Therapy After Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia (CML)
Study Start Date :
Dec 1, 2008
Actual Primary Completion Date :
Sep 1, 2014
Actual Study Completion Date :
Sep 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: Azacytidine Maintenance after allotx

Busulfan + Fludarabine + ATG + Azacytidine after allogeneic stem cell transplantation (allotx)

Drug: Fludarabine
40 mg/m^2 by vein over 60 minutes on Day -5 through Day -2.
Other Names:
  • Fludarabine Phosphate
  • Drug: Busulfan
    Busulfan administered at the dose calculated to achieve an area under curve (AUC) of 4000 µMol-min + 12% based on the pharmacokinetic studies (days -5, -4, -3, and -2).
    Other Names:
  • Busulfex
  • Myleran
  • Drug: Thymoglobulin
    2.5 mg/kg by vein over about 4-6 hours on Day -3 through Day -1.
    Other Names:
  • Antithymocyte globulin
  • ATG
  • Drug: Azacitidine
    Start cycles of 32 mg/m^2 daily as an injection under the skin once a day over 5 days in a row, starting about 5 weeks after the transplant. This may be repeated once a month for up to 4 months after the transplant.
    Other Names:
  • 5-Azacitidine
  • 5-Aza
  • 5-AZC
  • Ladakamycin
  • NSC-102816
  • Vidaza
  • Procedure: Stem Cell Transplant
    Stem cell infusion on day 0 administered by vein after collected from donor.
    Other Names:
  • allotx
  • allogeneic stem cell transplantation
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Molecular Response [12 month post BMT]

      Molecular Remission defined as two consecutive bone marrow samples done one month apart with negative PCR( polymerase chain reaction) tor CML.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Patients with age <= 75 years with CML in first chronic phase, which has failed to achieve a cytogenetic or molecular complete remission or has progressed after imatinib treatment. Criteria for failure are the international consensus criteria (Appendix H). Patients intolerant to tyrosine kinase inhibitor therapy are also eligible.

    2. Patients with age <= 75 with CML in accelerated phase or blast crisis that have <= 15% blasts in the blood and bone marrow at study entry.

    3. Donor: HLA-compatible related (HLA-A, -B, -DRB1 matched or with one-antigen mismatch) or HLA-compatible unrelated (HLA-A, -B, -C and -DRB1 matched or with one-antigen mismatch).

    4. Age 18 to 75 years.

    5. Zubrod performance status <= 2.

    6. Left ventricular ejection fraction => 40%.

    7. Pulmonary function test within the following parameters: 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.

    8. Serum creatinine < 1.5 mg/dL or creatinine clearance greater or equal than 40 cc/min.

    9. Serum direct bilirubin < 1.5 mg/dL (unless Gilbert's syndrome)

    10. Serum glutamate pyruvate transaminase (SGPT) <= 200 IU/L unless related to patient's malignancy.

    11. Patients treated with any tyrosine kinase inhibitor, interferon or any experimental therapy are eligible.

    12. Patients with age <75 years with CML in second or subsequent chronic phase.

    Exclusion Criteria:
    1. Uncontrolled infection, not responding to appropriate antimicrobial agents after seven days of therapy.

    2. Pleural/pericardial effusion or ascites estimated to be >1L.

    3. HIV-positive.

    4. Breast feeding or pregnancy. Pregnancy means a positive beta human chorionic gonadotropin (HCG) test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization.

    5. Known or suspected hypersensitivity to azacitidine or mannitol.

    6. Patients with advanced malignant hepatic tumors.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Texas MD Anderson Cancer Center Houston Texas United States 77030

    Sponsors and Collaborators

    • M.D. Anderson Cancer Center
    • National Cancer Institute (NCI)
    • Celgene Corporation

    Investigators

    • Principal Investigator: Richard E. Champlin, MD, BS, M.D. Anderson Cancer Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT00813124
    Other Study ID Numbers:
    • 2008-0087
    • NCI-2012-02122
    First Posted:
    Dec 22, 2008
    Last Update Posted:
    Feb 11, 2021
    Last Verified:
    Jan 1, 2021

    Study Results

    Participant Flow

    Recruitment Details Recruitment Period: December 17, 2008 to February 27, 2014. All recruitment done at The University of Texas (UT) MD Anderson Cancer Center.
    Pre-assignment Detail
    Arm/Group Title Azacitidine Post Transplant
    Arm/Group Description Fludarabine 40 mg/m^2 intravenous (IV) Day -5 to Day -2; Busulfan dose calculated to achieve area under curve (AUC) of 4000 µMol-min + 12% based on pharmacokinetic studies (days -5, -4, -3, and -2); Thymoglobulin: 2.5 mg/kg IV on Day -3 to Day -1; Azacitidine 32 mg/m^2 subcutaneous daily for 5 days starting 5 weeks after transplant, repeated monthly up to 4 months. Allogeneic stem cell infusion (allotx) on day 0.
    Period Title: Overall Study
    STARTED 24
    COMPLETED 12
    NOT COMPLETED 12

    Baseline Characteristics

    Arm/Group Title Azacytidine Maintenance After Allotx
    Arm/Group Description Fludarabine 40 mg/m^2 intravenous (IV) Day -5 to Day -2; Busulfan dose calculated to achieve area under curve (AUC) of 4000 µMol-min + 12% based on pharmacokinetic studies (days -5, -4, -3, and -2); Thymoglobulin: 2.5 mg/kg IV on Day -3 to Day -1; Azacitidine 32 mg/m^2 subcutaneous daily for 5 days starting 5 weeks after transplant, repeated monthly up to 4 months. Allogeneic stem cell infusion (allotx) on day 0.
    Overall Participants 24
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    23
    95.8%
    >=65 years
    1
    4.2%
    Sex: Female, Male (Count of Participants)
    Female
    12
    50%
    Male
    12
    50%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    8.3%
    Not Hispanic or Latino
    20
    83.3%
    Unknown or Not Reported
    2
    8.3%
    Region of Enrollment (participants) [Number]
    United States
    24
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Molecular Response
    Description Molecular Remission defined as two consecutive bone marrow samples done one month apart with negative PCR( polymerase chain reaction) tor CML.
    Time Frame 12 month post BMT

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Azacytidine Maintenance After Allotx
    Arm/Group Description Fludarabine 40 mg/m^2 intravenous (IV) Day -5 to Day -2; Busulfan dose calculated to achieve area under curve (AUC) of 4000 µMol-min + 12% based on pharmacokinetic studies (days -5, -4, -3, and -2); Thymoglobulin: 2.5 mg/kg IV on Day -3 to Day -1; Azacitidine 32 mg/m^2 subcutaneous daily for 5 days starting 5 weeks after transplant, repeated monthly up to 4 months. Allogeneic stem cell infusion (allotx) on day 0.
    Measure Participants 12
    Complete Response
    8
    33.3%
    Partial Response
    0
    0%
    Progressive Disease
    4
    16.7%

    Adverse Events

    Time Frame Adverse event data collected through four treatment cycles of 28 days.
    Adverse Event Reporting Description
    Arm/Group Title Azacytidine Maintenance After Allotx
    Arm/Group Description Fludarabine 40 mg/m^2 intravenous (IV) Day -5 to Day -2; Busulfan dose calculated to achieve area under curve (AUC) of 4000 µMol-min + 12% based on pharmacokinetic studies (days -5, -4, -3, and -2); Thymoglobulin: 2.5 mg/kg IV on Day -3 to Day -1; Azacitidine 32 mg/m^2 subcutaneous daily for 5 days starting 5 weeks after transplant, repeated monthly up to 4 months. Allogeneic stem cell infusion (allotx) on day 0.
    All Cause Mortality
    Azacytidine Maintenance After Allotx
    Affected / at Risk (%) # Events
    Total 2/24 (8.3%)
    Serious Adverse Events
    Azacytidine Maintenance After Allotx
    Affected / at Risk (%) # Events
    Total 14/24 (58.3%)
    Blood and lymphatic system disorders
    Delayed engraftment 1/24 (4.2%)
    Febrile neutropenia 1/24 (4.2%)
    Low granulocyte 1/24 (4.2%)
    Infections and infestations
    Bacterial 6/24 (25%)
    Fungal 1/24 (4.2%)
    Viral 5/24 (20.8%)
    Investigations
    ALT increased 2/24 (8.3%)
    Low platelet 2/24 (8.3%)
    Metabolism and nutrition disorders
    Hyperglycemia 1/24 (4.2%)
    Musculoskeletal and connective tissue disorders
    Generalized muscle weakness 2/24 (8.3%)
    Psychiatric disorders
    Confusion 1/24 (4.2%)
    Renal and urinary disorders
    Hemorrhagic Cystitis 1/24 (4.2%)
    Skin and subcutaneous tissue disorders
    Rash 2/24 (8.3%)
    Vascular disorders
    Thromboembolic event 2/24 (8.3%)
    Other (Not Including Serious) Adverse Events
    Azacytidine Maintenance After Allotx
    Affected / at Risk (%) # Events
    Total 24/24 (100%)
    Blood and lymphatic system disorders
    Low granulocyte 1/24 (4.2%)
    Eye disorders
    Blurred vision 1/24 (4.2%)
    Dry eye 2/24 (8.3%)
    Gastrointestinal disorders
    Abdominal pain 2/24 (8.3%)
    Diarrhea 7/24 (29.2%)
    Nausea 22/24 (91.7%)
    Oral mucositis 14/24 (58.3%)
    General disorders
    Fever 18/24 (75%)
    Flu like syndrome 1/24 (4.2%)
    Fluid overload 5/24 (20.8%)
    Infections and infestations
    Bacterial 4/24 (16.7%)
    Viral 12/24 (50%)
    Injury, poisoning and procedural complications
    Bruising 1/24 (4.2%)
    Investigations
    ALT increased 7/24 (29.2%)
    Creatinine increased 3/24 (12.5%)
    Low platelet 2/24 (8.3%)
    T bilirubin increased 5/24 (20.8%)
    Metabolism and nutrition disorders
    Anorexia 1/24 (4.2%)
    Hyperglycemia 1/24 (4.2%)
    Musculoskeletal and connective tissue disorders
    Bone pain 3/24 (12.5%)
    Nervous system disorders
    Dizziness 1/24 (4.2%)
    Headache 5/24 (20.8%)
    Renal and urinary disorders
    Hemorrhagic Cystitis 2/24 (8.3%)
    Respiratory, thoracic and mediastinal disorders
    Broncholitis obliterans 1/24 (4.2%)
    Skin and subcutaneous tissue disorders
    Rash 10/24 (41.7%)
    Vascular disorders
    Hypertension 2/24 (8.3%)

    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/Title Richard E. Champlin, MD/Chair, Stem Cell Transplantation
    Organization University of Texas (UT) MD Anderson Cancer Center
    Phone 713-792-3618
    Email rchampli@mdanderson.org
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT00813124
    Other Study ID Numbers:
    • 2008-0087
    • NCI-2012-02122
    First Posted:
    Dec 22, 2008
    Last Update Posted:
    Feb 11, 2021
    Last Verified:
    Jan 1, 2021