Busulfan, Fludarabine, Clofarabine With Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia

Busulfan-Fludarabine-Clofarabine With Allogeneic Stem Cell Transplantation for Advanced Refractory Acute Myeloid Leukemia, Myelodysplastic Syndrome, and Advanced, Gleevec Refractory Chronic Myeloid Leukemia. A Randomized Phase II Study.

The goal of this clinical research study is to find the best dose of clofarabine and fludarabine that can be given with busulfan followed by an allogeneic blood stem cell transplant. Researchers will study whether this combination can help to control the disease, and look at the safety of this combination. Researchers also want to find out if combining busulfan with clofarabine alone or combining busulfan with both fludarabine and clofarabine will improve the treatment, compared with the previous standard method using busulfan and fludarabine alone.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Chronic Myeloid Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Drug: Clofarabine; Drug: Busulfan; Drug: Fludarabine; Other: Stem Cell Infusion; Drug: Thymoglobulin (ATG); Drug: Filgrastim

Detailed Description

Busulfan is a chemotherapy drug that kills cancer cells by binding to DNA (the genetic material of cells). Clofarabine is designed to interfere with the growth and development of cancer cells. Fludarabine is designed to interfere with DNA repair enzymes so that the leukemic cells cannot repair damaged DNA. This may increase the likelihood of the cell dying. These drugs are being given to try to kill cancerous cells and weaken your immune system in order to lower the risk of stem cell transplant rejection.

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to 1 of 4 study groups. Three (3) of the groups will receive busulfan, fludarabine, and clofarabine at different dose levels. The 4th group will only receive busulfan and clofarabine. As the study continues, participants will be assigned using a method called adaptive randomization. This method works by increasing the chances of being assigned to the group that has had the best results in the study so far. You will know which group you have been assigned to.

Participants will receive busulfan, fludarabine, and/or clofarabine once a day for 4 doses. 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 needed to reach a target blood level of busulfan. You will have a total of about 6 and 1/2 tablespoons of blood drawn over time to check your busulfan blood levels following one or more of the busulfan treatments. Up to 11 samples of blood will be drawn to check your blood levels of busulfan during the next 11 hours following the test dose and the first high-dose busulfan treatment. Each sample will require about 1 teaspoon of blood. A heparin lock line will be placed in a vein to lower the number of needle sticks needed for these draws. 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.

Clofarabine and fludarabine (if applicable) will be given through a central venous catheter (CVC) over 1 hour, once a day, for 4 days. Busulfan will also be given through the CVC over 3 hours.

If you are going to be receiving a transplant from an HLA-nonidentical or unrelated donor, you will also receive thymoglobulin (ATG) over 4 hours on the 3 days before the transplant to further weaken your immune system to reduce the risk of rejecting of the transplant. After the transplant, you will receive tacrolimus, methotrexate, or other immunosuppressive (lowering the immune system) drugs in the standard manner to lower the risk of graft-vs-host disease (GVHD), a reaction of the donor's immune cells against the recipient's body.

The allogeneic stem cells (bone marrow or peripheral blood stem cells) will also be given through the CVC. You will receive the drug G-CSF (filgrastim) as an injection under the skin once a day, starting 1 week after the transplant, until your blood cell levels return to normal.

Patients usually stay in the hospital for about 4 weeks after stem cell transplantation. After you are released from the hospital, you will continue to be monitored as an outpatient for infections and transplant-related complications for at least 100 days after the transplant.

You will have blood tests (about 4 tablespoons of blood) and bone marrow aspirations performed at 1, 3, 6, and 12 months after the transplant, to check if the disease is in remission (has not come back). Your health status will be followed with the help of your local doctor to find out if the leukemia or MDS comes back, as well as to check the length of your survival.

This is an investigational study. All of the drugs used in this study are approved by the FDA for treatment of cancer. Busulfan has been approved for use in stem cell transplantation. The use of these drugs together with stem cell transplant is experimental. Up to 70 patients will take part in this study. All will be enrolled at the M. D. Anderson Cancer Center.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • UT MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 60 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis or 1) Acute myeloid leukemia past first remission, in first or subsequent relapse, or induction failures, 2) Myelodysplastic syndromes with intermediate or high risk International Prognostic Scoring System score (IPSS scores) (16), and having failed previous chemotherapy, or 3) Chronic Myeloid Leukemia, Philadelphia-chromosome positive and having failed / being resistant to therapy based on Gleevec or other tyrosine kinase inhibitors.
2. Patient has not been administered intensive systemic chemotherapeutic drugs within 21 days prior to trial enrollment (bone marrow transplant (BMT) Day -9). Gleevec, alternative tyrosine kinase inhibitors, other nonmyelosuppressive agents, low dose cytarabine, hydroxyurea is permitted if indicated to control the leukemia. All tyrosine inhibitor- or other non-myelosuppressive agents have to be terminated at least one week prior to admission for this treatment.
3. No uncontrolled infection. Protocol principal investigator (PI) will be final arbiter if there is uncertainty regarding whether a previous infection is resolved on appropriate antibiotics therapy.
4. age </= 60
5. A related or unrelated donor who is HLA-matched or mismatched in 1 HLA, A, B, C, DR or DQ locus is acceptable (i.e. at least a 9/10 matched related or unrelated donor, matched with molecular high-resolution technique per current standard for the BMT program).
6. ZUBROD performance status <2
7. Life expectancy is not severely limited by concomitant illness.
8. Left ventricular ejection fraction >/=45% No uncontrolled arrhythmias or symptomatic cardiac disease.
9. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO) >/= 50% of expected corrected for hemoglobin. In patients </= 7 years pulmonary function will be assessed per pediatric BMT routine
10. Serum creatinine </= 1.5 mg%.
11. Serum glutamic pyruvic transaminase (SGPT) </= 200 IU/ml, serum bilirubin and alkaline phosphatase within accepted laboratory standard normal limits or considered not clinically significant. No evidence of chronic active hepatitis or cirrhosis. If positive hepatitis serology, discuss with Study Chairman and perform liver biopsy pror to determining study eligibility.
12. Female patient is not pregnant (negative human chorionic gonadotropin (hCG) pregnancy test in all women of child-bearing-potential in accordance with departmental routine).
13. Patient or patient's legal representative, parent(s) or guardian able to sign informed consent.

Exclusion Criteria:

1. Effusion or ascites estimated to be >1L prior to drainage.
2. HIV-positive.
3. Hepatitis C or HBsAg positive
4. Prior stem cell transplant after a myeloablative conditioning program (such as busulfan-based using a total dose of >/= 12 mg/kg given by mouth or >/= 10 mg/kg IV, or a total-body irradiation-based program.
5. Active or prior Central Nervous System (CNS) leukemia
6. Biphenotypic acute leukemia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Arm 1: Busulfan + Fludarabine (30 mg/m^2) + Clofarabine; 4-day Treatment Period Day -6 to Day -2: Busulfan 30 mg/m^2 intravenous (IV) Daily + Fludarabine 30 mg/m^2 IV Daily; + Clofarabine 10 mg/m^2 IV Daily; Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.	Drug: Clofarabine; Day -6 to Day -3 for Arm 1 = 10 mg/m^2 intravenous (IV) Daily; Arm 2 = 20 mg/m^2 IV Daily; Arm 3 = 30 mg/m^2 IV Daily; Arm 4 = 40 mg/m^2 IV Daily; Other Names: Clofarex; Clolar; Drug: Busulfan; Day -6 to Day -3 for Arm 1: 30 mg/m^2 IV Daily; Arm 2: 20 mg/m^2 IV Daily; Arm 3: 10 mg/m^2 IV Daily; Arm 4: 40 mg/m^2 IV Daily. Test dose Day -8 32 mg/ m^2 IV over 45 min, rest on Day -7.; Other Names: Busulfex; Myleran; Drug: Fludarabine; Day -6 to Day -3 for Arm 1: 30 mg/m^2 IV Daily; Arm 2: 20 mg/m^2 IV Daily; Arm 3: 10 mg/m^2 IV Daily; Other Names: Fludara; Fludarabine Phosphate; Other: Stem Cell Infusion; Day 0 stem cell infusion (Bone marrow or peripheral blood progenitor cells (PBPC)); Other Names: BMT; Bone Marrow Transplant; PBPC; peripheral blood progenitor cells; Unstimulated bone marrow transplant; bone marrow transplantation; ABM transplantations; autologous bone marrow transplantation; Drug: Thymoglobulin (ATG); Day -3 to Day -1 at 0.5 mg/kg IV on Day -3; 1.5 mg/kg on Day -2 and 2.0 mg/kg on Day -1.; Other Names: Antithymocyte Globulin; Thymoglobulin; Drug: Filgrastim; Subcutaneous injection daily, starting 1 week after Stem Cell Transplant.; Other Names: G-CSF; Granulocyte colony-stimulating factor; GCSF
EXPERIMENTAL: Arm 2: Busulfan + Fludarabine (20 mg/m^2) + Clofarabine; 4-day Treatment Period Day -6 to Day -2: Busulfan 20 mg/m^2 IV + Fludarabine 20 mg/m^2 IV Daily + Clofarabine 20 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.	Drug: Clofarabine; Day -6 to Day -3 for Arm 1 = 10 mg/m^2 intravenous (IV) Daily; Arm 2 = 20 mg/m^2 IV Daily; Arm 3 = 30 mg/m^2 IV Daily; Arm 4 = 40 mg/m^2 IV Daily; Other Names: Clofarex; Clolar; Drug: Busulfan; Day -6 to Day -3 for Arm 1: 30 mg/m^2 IV Daily; Arm 2: 20 mg/m^2 IV Daily; Arm 3: 10 mg/m^2 IV Daily; Arm 4: 40 mg/m^2 IV Daily. Test dose Day -8 32 mg/ m^2 IV over 45 min, rest on Day -7.; Other Names: Busulfex; Myleran; Drug: Fludarabine; Day -6 to Day -3 for Arm 1: 30 mg/m^2 IV Daily; Arm 2: 20 mg/m^2 IV Daily; Arm 3: 10 mg/m^2 IV Daily; Other Names: Fludara; Fludarabine Phosphate; Other: Stem Cell Infusion; Day 0 stem cell infusion (Bone marrow or peripheral blood progenitor cells (PBPC)); Other Names: BMT; Bone Marrow Transplant; PBPC; peripheral blood progenitor cells; Unstimulated bone marrow transplant; bone marrow transplantation; ABM transplantations; autologous bone marrow transplantation; Drug: Thymoglobulin (ATG); Day -3 to Day -1 at 0.5 mg/kg IV on Day -3; 1.5 mg/kg on Day -2 and 2.0 mg/kg on Day -1.; Other Names: Antithymocyte Globulin; Thymoglobulin; Drug: Filgrastim; Subcutaneous injection daily, starting 1 week after Stem Cell Transplant.; Other Names: G-CSF; Granulocyte colony-stimulating factor; GCSF
EXPERIMENTAL: Arm 3: Busulfan + Fludarabine (10 mg/m^2) + Clofarabine; 4-day Treatment Period Day -6 to Day -2: Busulfan 10 mg/m^2 IV Daily + Fludarabine 10 mg/m^2 IV Daily + Clofarabine 30 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.	Drug: Clofarabine; Day -6 to Day -3 for Arm 1 = 10 mg/m^2 intravenous (IV) Daily; Arm 2 = 20 mg/m^2 IV Daily; Arm 3 = 30 mg/m^2 IV Daily; Arm 4 = 40 mg/m^2 IV Daily; Other Names: Clofarex; Clolar; Drug: Busulfan; Day -6 to Day -3 for Arm 1: 30 mg/m^2 IV Daily; Arm 2: 20 mg/m^2 IV Daily; Arm 3: 10 mg/m^2 IV Daily; Arm 4: 40 mg/m^2 IV Daily. Test dose Day -8 32 mg/ m^2 IV over 45 min, rest on Day -7.; Other Names: Busulfex; Myleran; Drug: Fludarabine; Day -6 to Day -3 for Arm 1: 30 mg/m^2 IV Daily; Arm 2: 20 mg/m^2 IV Daily; Arm 3: 10 mg/m^2 IV Daily; Other Names: Fludara; Fludarabine Phosphate; Other: Stem Cell Infusion; Day 0 stem cell infusion (Bone marrow or peripheral blood progenitor cells (PBPC)); Other Names: BMT; Bone Marrow Transplant; PBPC; peripheral blood progenitor cells; Unstimulated bone marrow transplant; bone marrow transplantation; ABM transplantations; autologous bone marrow transplantation; Drug: Thymoglobulin (ATG); Day -3 to Day -1 at 0.5 mg/kg IV on Day -3; 1.5 mg/kg on Day -2 and 2.0 mg/kg on Day -1.; Other Names: Antithymocyte Globulin; Thymoglobulin; Drug: Filgrastim; Subcutaneous injection daily, starting 1 week after Stem Cell Transplant.; Other Names: G-CSF; Granulocyte colony-stimulating factor; GCSF
EXPERIMENTAL: Arm 4: Busulfan + Clofarabine; 4-day Treatment Period Day -6 to Day -2: Busulfan 40 mg/m^2 IV Daily + Clofarabine 40 mg/m^2 IV Daily. Thymoglobulin Day -3 to Day -1, and Stem Cell Infusion Day 0.	Drug: Clofarabine; Day -6 to Day -3 for Arm 1 = 10 mg/m^2 intravenous (IV) Daily; Arm 2 = 20 mg/m^2 IV Daily; Arm 3 = 30 mg/m^2 IV Daily; Arm 4 = 40 mg/m^2 IV Daily; Other Names: Clofarex; Clolar; Drug: Busulfan; Day -6 to Day -3 for Arm 1: 30 mg/m^2 IV Daily; Arm 2: 20 mg/m^2 IV Daily; Arm 3: 10 mg/m^2 IV Daily; Arm 4: 40 mg/m^2 IV Daily. Test dose Day -8 32 mg/ m^2 IV over 45 min, rest on Day -7.; Other Names: Busulfex; Myleran; Other: Stem Cell Infusion; Day 0 stem cell infusion (Bone marrow or peripheral blood progenitor cells (PBPC)); Other Names: BMT; Bone Marrow Transplant; PBPC; peripheral blood progenitor cells; Unstimulated bone marrow transplant; bone marrow transplantation; ABM transplantations; autologous bone marrow transplantation; Drug: Thymoglobulin (ATG); Day -3 to Day -1 at 0.5 mg/kg IV on Day -3; 1.5 mg/kg on Day -2 and 2.0 mg/kg on Day -1.; Other Names: Antithymocyte Globulin; Thymoglobulin; Drug: Filgrastim; Subcutaneous injection daily, starting 1 week after Stem Cell Transplant.; Other Names: G-CSF; Granulocyte colony-stimulating factor; GCSF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Related Mortality	Number of participants with treatment related mortality (death) within the first 30 days following transplantation.	First 30 Days

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: Genzyme, a Sanofi Company

Publications and helpful links

General Publications

• Andersson BS, Valdez BC, de Lima M, Wang X, Thall PF, Worth LL, Popat U, Madden T, Hosing C, Alousi A, Rondon G, Kebriaei P, Shpall EJ, Jones RB, Champlin RE. Clofarabine +/- fludarabine with once daily i.v. busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS. Biol Blood Marrow Transplant. 2011 Jun;17(6):893-900. doi: 10.1016/j.bbmt.2010.09.022. Epub 2010 Oct 11.

Helpful Links

• UT MD Anderson Cancer Website

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (ACTUAL): March 1, 2013
• Study Completion (ACTUAL): March 1, 2013

Study Registration Dates

• First Submitted: May 3, 2007
• First Submitted That Met QC Criteria: May 3, 2007
• First Posted (ESTIMATE): May 4, 2007

Study Record Updates

• Last Update Posted (ACTUAL): January 26, 2021
• Last Update Submitted That Met QC Criteria: January 6, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; Gleevec; AML; MDS; Chronic Myeloid Leukemia; CML; Myelodysplastic Syndrome; Fludarabine; Fludara; Fludarabine Phosphate; Busulfan; Busulfex; Stem Cell; Imatinib Mesylate; Clofarabine; ASCT; Clolar; Allogeneic stem cell transplantation; Myleran; Clofarex
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Adjuvants, Immunologic; Clofarabine; Lenograstim; Fludarabine; Fludarabine phosphate; Busulfan; Thymoglobulin; Antilymphocyte Serum
• Other Study ID Numbers: 2006-0200