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

NCT01471444 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 2011-0628NCI-2012-00038
• Study Type: interventional
• Target: 256
• Locations: 1 country
• Sites: 1

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.

Conditions

Disorder Related to Bone Marrow Transplantation; Leukemia; Transplantation Infection

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; Clofarabine; Clofarex; Clolar; Busulfan; Busulfex; Myleran; Thymoglobulin; ATG; Antithymocyte Globulin; Methotrexate; Tacrolimus; Prograf

Outcome Measures

Primary Outcomes (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.

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

Secondary Outcomes (3)

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

  Post transplant after 1, 3 and 5 years

• 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.

  100 days post transplant

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

  100 day Post Transplant

Study Arms (2)

Flu + Bu

EXPERIMENTAL

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; Drug: Busulfan; Drug: Thymoglobulin; Procedure: Stem Cell Infusion; Drug: Tacrolimus; Drug: Methotrexate

Flu +Clo + Bu

EXPERIMENTAL

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; Drug: Clofarabine; Drug: Busulfan; Drug: Thymoglobulin; Procedure: Stem Cell Infusion; Drug: Tacrolimus; Drug: Methotrexate

Interventions

Fludarabine DRUG

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.

Also known as: Fludarabine Phosphate, Fludara

Flu + Bu; Flu +Clo + Bu

Clofarabine DRUG

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

Also known as: Clofarex, Clolar

Flu +Clo + Bu

Busulfan DRUG

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).

Also known as: Busulfex, Myleran

Flu + Bu; Flu +Clo + Bu

Thymoglobulin DRUG

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.

Also known as: ATG, Antithymocyte Globulin

Flu + Bu; Flu +Clo + Bu

Stem Cell Infusion PROCEDURE

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

Also known as: Bone marrow transplant

Flu + Bu; Flu +Clo + Bu

Tacrolimus DRUG

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.

Also known as: Prograf

Flu + Bu; Flu +Clo + Bu

Methotrexate DRUG

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

Flu + Bu; Flu +Clo + Bu

Eligibility Criteria

• Age: 3 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• Sanofi: collaborator

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Leukemia; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Graft vs Host Disease

Interventions

fludarabine; fludarabine phosphate; Clofarabine; Busulfan; thymoglobulin; Antilymphocyte Serum; Bone Marrow Transplantation; Tacrolimus; Methotrexate

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Nucleotides; Ribonucleotides; Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Tissue Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Macrolides; Lactones; Aminopterin; Pterins; Pteridines

Results Point of Contact

• Title: Richard Champlin, MD / Stem Cell Transplantation
• Organization: University of Texas MD Anderson Cancer Center

rchampli@mdanderson.org

713-792-3618

Study Officials

• Richard E. Champlin, BS,MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 10, 2011
• First Posted: November 15, 2011
• Study Start: November 2, 2011
• Primary Completion: December 14, 2020
• Study Completion: December 14, 2020
• Last Updated: December 16, 2021
• Results First Posted: December 16, 2021

Record last verified: 2021-09

Locations

US (1)