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A Randomized Study of Once Daily Fludarabine-Clofarabine Versus Fludarabine Alone Combined With Intervenous Busulfan Followed by Allogeneic Hemopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Phase 3
3 Years
70 Years
Open (Enrolling)
Disorder Related to Bone Marrow Transplantation, Leukemia, Transplantation Infection

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Trial Information

A Randomized Study of Once Daily Fludarabine-Clofarabine Versus Fludarabine Alone Combined With Intervenous Busulfan Followed by Allogeneic Hemopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Busulfan is designed to kill cancer cells by binding to DNA (the genetic material of cells),
which may cause cancer cells to die. Busulfan is commonly used in stem cell

Clofarabine is designed to interfere with the growth and development of cancer cells.

Fludarabine is designed to interfere with the DNA of cancer cells, which may cause the
cancer cells to die.

Study Groups:

You will be randomly assigned (as in the toss of a coin) to 1 of 2 study groups.

- Group 1 will receive busulfan, fludarabine, and clofarabine.

- Group 2 will receive busulfan and fludarabine.

Both groups will have a stem cell transplant. The stem cells will be given by vein. The
cells will travel to your bone marrow where they are designed to make healthy, new blood
cells after several weeks.

For a stem cell transplant, the days before you receive your stem cells are called minus
days. The day you receive the stem cells is called Day 0. The days after you receive the
stem cells are called plus days.

Study Drug Administration and Procedures:

Both groups will receive a "test" dose of busulfan by vein over about 45 minutes to 1 hour.
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 determine the amount 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 8 days before your stem cell

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 also help determine your dose of busulfan. 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 -6, which
is 6 days before the transplant).

A 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 for technical or
scheduling reasons, you will receive the standard fixed dose of busulfan.

On Days -6 through -3, you will receive fludarabine by vein over 1 hour, then clofarabine
(if you are in Group 1) by vein over 1 hour, then busulfan by vein over 3 hours.

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.

If you are going to be receiving a transplant from an HLA-nonidentical or unrelated donor,
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.

You will receive filgrastim as an injection under the skin 1 time a day, starting 1 week
after the transplant, until your blood cell levels return to normal. Filgrastim is designed
to help with the growth of white blood cells.

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, for routine tests, to check your blood counts, kidney and liver function, and to
check for infections.

As part of standard care, you will remain in the hospital for about 3-4 weeks after
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 3 months after
transplant. During this time, you will return to the clinic at least 1 time each week. 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

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

Around 14-30 days after the transplant (when the transplant "engrafts", or "takes"), you
will have a bone marrow aspirate to check the status of the disease.

Around Day 30, and about 3, 6, and 12 months after the transplant, the following tests and
procedures will be performed:

- You will have a physical exam, including measurement of your vital signs (blood
pressure, heart rate, temperature, and breathing rate).

- You will be asked about how you are feeling and about any side effects you may be

- Blood (about 2 teaspoons) will be drawn to see how well the transplant has taken.

- You will have a bone marrow aspiration to check the status of the disease. To collect
a bone marrow aspiration, an area of the hip or other site is numbed with anesthetic,
and a small amount of bone marrow is withdrawn through a large needle.

Length of Study:

You will be taken off study 5 years after the end of treatment. You may be taken off study
early if the disease gets worse, if you have any intolerable side effects, of if you are
unable to follow study directions.

You should talk to the study doctor if you want to leave the study early. 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.

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 and fludarabine are both FDA approved and
commercially available for the treatment of AML and MDS. Clofarabine is FDA approved for
treating other types of cancer, but is being used in AML and MDS for research only. The use
of these study drugs together at the dose level used in this study is investigational.

Up to 250 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Patients must have one of the following hematologic malignancies: a) Acute myeloid
leukemia (AML) any stage and cytogenetic risk-group with the only exception being
that patients with AML and favorable cytogenetics (t(8;21, inv 16, or t(15;17) who
achieve complete remission with one course of induction chemotherapy are not
eligible. Patients with treatment related AML are eligible. b) Myelodysplastic
syndromes (MDS) with intermediate or high risk International Prognostic Scoring
System score (IPSS scores) or treatment related MDS. Patients with low risk MDS are
eligible if they fail to respond to hypomethylating agent therapy such as azacitidine
or decitabine.

2. Age 3-70 years old. Eligibility for pediatric patients will be determined in
conjunction with an MDACC pediatrician.

3. Performance score of >/= 60 by Karnofsky or PS 0 to 2 (ECOG) (age > 12 years), or
Lansky Play-Performance Scale >/= 60 or greater (age <12 years).

4. Negative Beta HCG test in a woman with child bearing potential, defined as not
post-menopausal for 12 months or no previous surgical sterilization. Women of child
bearing potential must be willing to use an effective contraceptive measure while on

5. Adequate major organ system function as demonstrated by: Left ventricular ejection
fraction of at least 40%.

6. Pulmonary function test (PFT) demonstrating a diffusion capacity of least 50%
predicted. For children saturation >/=92% on room air by pulse oximetry.

7. Creatinine < 1.5 mg/dL. If question about renal function discuss with study chairman
and do 24 hour creatinine clearance (clearance should be >50 ml/min).

8. Bilirubin < to 2.0 x normal (except Gilbert's Syndrome). SGPT (ALT) < 200. No
evidence of chronic active hepatitis or cirrhosis.

9. Histocompatible stem cell donor: Patients must have an HLA matched related or
unrelated donor (HLA A, B, C and DR) willing to donate for allogenic hematopoietic
transplantation. High resolution allele level typing is required for donors other
than genotypically identical siblings.

10. No uncontrolled infection. Protocol PI or designé will be final arbiter if there is
uncertainty regarding whether a previous infection is controlled on appropriate
(antibiotic) therapy.

11. Patient or patient's legal representative, parent(s) or guardian able to sign
informed consent.

Exclusion Criteria:

1. Positive for HIV, HBsAg, HCV or other viral hepatitis or cirrhosis from any cause.

2. Prior allogenic or autologous stem cell transplant using a myeloablative busulfan or
total body radiation containing conditioning regimen defined as busulfan-based using
a total dose of >/=12 mg/kg given by mouth or >/=10 mg/kg given IV; or a total-body
irradiation (> 4 Gy).

3. Active or prior CNS leukemia, unless in complete remission for at least 3 months.

4. Previous therapeutic XRT to the liver as part of involved-field radiation.

5. History of serious chronic mental disorder or drug-abuse accompanied by documented
problems of compliance with therapeutic programs.

6. Lack of care-giver for the early (100-day) post-transplant period.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-Free Survival (PFS)

Outcome Description:

Progression-free survival defined as the time from date of transplant to death from any cause or disease progression. Bone marrow aspiration used for disease status.

Outcome Time Frame:

30 Days

Safety Issue:


Principal Investigator

Richard E. Champlin, MD,BS

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center


United States: Institutional Review Board

Study ID:




Start Date:

November 2011

Completion Date:

Related Keywords:

  • Disorder Related to Bone Marrow Transplantation
  • Leukemia
  • Transplantation Infection
  • Blood And Marrow Transplantation
  • Leukemia
  • Allogeneic hematopoietic stem cell transplantation
  • Acute myeloid leukemia
  • AML
  • Myelodysplastic syndrome
  • MDS
  • Progression free survival
  • Rate of engraftment
  • Toxicity
  • Relapse rate
  • Graft-vs-host disease
  • GvHD
  • Progression-free survival
  • PFS
  • Overall survival
  • OS
  • Fludarabine
  • Fludarabine Phosphate
  • Fludara
  • Clofarabine
  • Clofarex
  • Clolar
  • Busulfan
  • Busulfex
  • Myleran
  • Thymoglobulin
  • ATG
  • Antithymocyte Globulin
  • Methotrexate
  • Tacrolimus
  • Prograf
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia



UT MD Anderson Cancer Center Houston, Texas  77030