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Disorder Related to Bone Marrow TransplantationPhase 3NCT01471444

Fludarabine-IV Busulfan ± Clofarabine and Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

A Phase 3 study testing Fludarabine, Clofarabine and Busulfan in people with Disorder Related to Bone Marrow Transplantation and Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

The goal of this clinical research study is to learn if combining busulfan with clofarabine and fludarabine can help control the disease better than the previous standard method (using busulfan and fludarabine alone) in patients with AML or MDS. The safety of this combination therapy will also be studied. Read more about this study

Who is it for?
Ages 3 to 70 years
What is being tested?
Fludarabine, Clofarabine and Busulfan
Could I receive a placebo?
No, everyone receives an active treatment
How many people
256 participants
Where
1 siteUnited States
Study dates
2 Nov 2011to 14 Dec 2020
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 3 to 70 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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.
  • Age 3-70 years old. Eligibility for pediatric patients will be determined in conjunction with an MDACC pediatrician.
  • 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).
  • 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 study.
  • Adequate major organ system function as demonstrated by: Left ventricular ejection fraction of at least 40%.
  • Pulmonary function test (PFT) demonstrating a diffusion capacity of least 50% predicted. For children </=7 years of age who are unable to perform PFT, oxygen saturation >/=92% on room air by pulse oximetry.
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  • 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).
  • Bilirubin < to 2.0 x normal (except Gilbert's Syndrome). SGPT (ALT) < 200. No evidence of chronic active hepatitis or cirrhosis.
  • Histocompatible stem cell donor: Patients must have an HLA matched related or unrelated donor (HLA A, B, C and DR) willing to donate for allogeneic hematopoietic transplantation. High resolution allele level typing is required for donors other than genotypically identical siblings.
  • 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.
  • Patient or patient's legal representative, parent(s) or guardian able to sign informed consent.

Who cannot join

  • Positive for HIV, HBsAg, HCV or other viral hepatitis or cirrhosis from any cause.
  • Prior allogeneic 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).
  • Active or prior CNS leukemia, unless in complete remission for at least 3 months.
  • Previous therapeutic XRT to the liver as part of involved-field radiation.
  • History of serious chronic mental disorder or drug-abuse accompanied by documented problems of compliance with therapeutic programs.
  • Lack of care-giver for the early (100-day) post-transplant period.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • University of Texas MD Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: 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)

The goal of this clinical research study is to learn if combining busulfan with clofarabine and fludarabine can help control the disease better than the previous standard method (using busulfan and fludarabine alone) in patients with AML or MDS. The safety of this combination therapy will also be studied.

Read the detailed description

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 transplantation.

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 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 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 having.
  • 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 having.
  • 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.

Being tested
Fludarabine, Clofarabine, Busulfan, Thymoglobulin, Stem Cell Infusion
Keywords
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
Medical subject headings
Leukemia, Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Graft vs Host Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • FludarabineDrug

    Also called Fludarabine Phosphate, Fludara

    Flu + Bu Group: 40 mg/m2 by vein on Days -6 through -3.

    Flu +Clo + Bu Group: 10 mg/m2 by vein on Days -6 through -3.

  • ClofarabineDrug

    Also called Clofarex, Clolar

    30 mg/m2 diluted in normal saline to produce a final concentration of 0.4 mg/mL, and infused on Days -6 through -3.

  • BusulfanDrug

    Also called Busulfex, Myleran

    Busulfan systemic exposure dose of 6000 µMol-min in normal saline over three (3) hours by vein every twenty-four (24) hours for four (4) consecutive days (days -6 to -3), starting immediately after the completion of Clofarabine. The dose on day -6 to -3 based on pharmacokinetic analysis of target AUC of 4,000 µMol-min ± 5% for 61-70 years of age (without Pharmacokinetics alternate dose 130 mg/m2).

  • ThymoglobulinDrug

    Also called ATG, Antithymocyte Globulin

    Both groups who receive a graft from an unrelated donor:

    0.5 mg/kg on day -3, 1.5 mg/kg on day -2 and 2.0 mg/kg on day -1. On day -3, administered after the chemotherapy is complete.

  • Stem Cell InfusionProcedure or surgery

    Also called Bone marrow transplant

    Cryopreserved bone marrow or peripheral blood progenitor cells infused on day 0.

  • TacrolimusDrug

    Also called Prograf

    Starting dose: 0.015 mg/kg (ideal body weight) as a 24 hour continuous infusion daily adjusted to achieve a therapeutic level of 5-15 ng/ml. Changed to oral dosing when tolerated and can be tapered off after day +90 if no graft versus host disease (GVHD) present.

  • MethotrexateDrug

    5 mg/m2 by vein on Days 1, 3, 6 and 11 post transplant.

Study groups in NCT01471444
Study groupRoleWhat they receive
Flu + BuExperimentalFludarabine 40 mg/m2 intravenous (IV) over 1 hour. Busulfan dose calculated to achieve a systemic exposure dose of 6000 µMol-min IV over 3 hours every 24 hours. Both delivered for 4 consecutive days (days -6 to -3). Stem cell transplant Day 0.
Receives: Drug: Fludarabine; Drug: Busulfan; Drug: Thymoglobulin; Procedure: Stem Cell Infusion; Drug: Tacrolimus; Drug: Methotrexate
Flu +Clo + BuExperimentalFludarabine 10 mg/m2 over 1 hour. Clofarabine 40 mg/m2 diluted in normal saline to produce a final concentration of 0.4 mg/mL, infused over 1 hour. Busulfan dose calculated to achieve a systemic exposure dose of 6000 µMol-min IV over 3 hours every 24 hours, immediately after Clofarabine. All delivered on 4 consecutive days (days -6 through -3). Stem cell transplant Day 0.
Receives: Drug: Fludarabine; Drug: Clofarabine; Drug: Busulfan; Drug: Thymoglobulin; Procedure: Stem Cell Infusion; Drug: Tacrolimus; Drug: Methotrexate

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-Free Survival (PFS)

    Number of events with progression free survival. (Progression is defined as more than 5% blast in the peripheral blood or bone marrow biopsy.) or expired from treatment related mortality post transplant.

    Measured: From day of transplant to disease of progression or death of any cause, whichever came first, assessed up to 5 years

Secondary outcomes (3)

  1. Overall Survival (OS) Post Transplant at 1, 3 and 5 Years

    Number of participants in the study who are alive and disease free at 1, 3 and 5 years post transplant.

    Measured: Post transplant after 1, 3 and 5 years

  2. Number of Participants in the Study Who Are With no Grade 3 or 4 Acute Graft-versus-host Disease at Any Time During the First 100 Days Post Transplant.

    Number of participants in the study who are with no Grade 3 or 4 acute graft-versus-host disease at any time during the first 100 days post transplant.

    Measured: 100 days post transplant

  3. Number of Participants With Non Relapse Mortality at 100 Day Post Transplant

    Number of participants expired from complications other than relapsed disease at 100 day Post Transplant.

    Measured: 100 day Post Transplant

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Nov 2011 (estimated)
  2. Study start2 Nov 2011
  3. Primary completion14 Dec 2020
  4. Study completion14 Dec 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
256 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01471444
Sponsor's protocol ID
2011-0628
Other IDs
NCI-2012-00038
Status last verified
Sep 2021
First submitted
10 Nov 2011
Last updated
16 Dec 2021
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Fludarabine, Clofarabine and Busulfan in people with Disorder Related to Bone Marrow Transplantation and Leukemia, run by M.D. Anderson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 16 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Dec 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-Free Survival (PFS) (time frame: From day of transplant to disease of progression or death of any cause, whichever came first, assessed up to 5 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01471444.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Dec 2021.

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