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

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ClinicalTrials.gov Identifier: NCT01471444
Recruitment Status : Completed
First Posted : November 15, 2011
Last Update Posted : December 17, 2020
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief 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.

Condition or disease Intervention/treatment Phase
Disorder Related to Bone Marrow Transplantation Leukemia Transplantation Infection Drug: Fludarabine Drug: Clofarabine Drug: Busulfan Drug: Thymoglobulin Procedure: Stem Cell Infusion Drug: Tacrolimus Drug: Methotrexate Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 256 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : November 2, 2011
Actual Primary Completion Date : December 14, 2020
Actual Study Completion Date : December 14, 2020


Arm Intervention/treatment
Experimental: Flu + Bu
Fludarabine 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.
Drug: Fludarabine

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.

Other Names:
  • Fludarabine Phosphate
  • Fludara

Drug: Busulfan
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).
Other Names:
  • Busulfex
  • Myleran

Drug: Thymoglobulin

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.

Other Names:
  • ATG
  • Antithymocyte Globulin

Procedure: Stem Cell Infusion
Cryopreserved bone marrow or peripheral blood progenitor cells infused on day 0.
Other Name: Bone marrow transplant

Drug: Tacrolimus
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.
Other Name: Prograf

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

Experimental: Flu +Clo + Bu
Fludarabine 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.
Drug: Fludarabine

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.

Other Names:
  • Fludarabine Phosphate
  • Fludara

Drug: Clofarabine
30 mg/m2 diluted in normal saline to produce a final concentration of 0.4 mg/mL, and infused on Days -6 through -3.
Other Names:
  • Clofarex
  • Clolar

Drug: Busulfan
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).
Other Names:
  • Busulfex
  • Myleran

Drug: Thymoglobulin

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.

Other Names:
  • ATG
  • Antithymocyte Globulin

Procedure: Stem Cell Infusion
Cryopreserved bone marrow or peripheral blood progenitor cells infused on day 0.
Other Name: Bone marrow transplant

Drug: Tacrolimus
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.
Other Name: Prograf

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




Primary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: 30 Days ]
    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.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 100 days post transplant ]
    The percentage 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   3 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 study.
  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 </=7 years of age who are unable to perform PFT, oxygen 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 allogeneic 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 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).
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01471444


Locations
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United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Sanofi
Investigators
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Principal Investigator: Richard E. Champlin, BS,MD M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01471444    
Other Study ID Numbers: 2011-0628
NCI-2012-00038 ( Registry Identifier: NCI CTRP )
First Posted: November 15, 2011    Key Record Dates
Last Update Posted: December 17, 2020
Last Verified: December 2020

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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:
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
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Vidarabine
Methotrexate
Fludarabine phosphate
Clofarabine
Fludarabine
Busulfan
Tacrolimus
Thymoglobulin
Antilymphocyte Serum
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists