Treosulfan and Fludarabine in Treating Younger Patients Who Are Undergoing a Donor Stem Cell Transplant for Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

• ClinicalTrials.gov Identifier: NCT00253513
• Recruitment Status: Completed
• First Posted: November 15, 2005
• Results First Posted: February 11, 2011
• Last Update Posted: June 1, 2012
• Sponsor: OHSU Knight Cancer Institute
• Collaborators: medac GmbH; National Cancer Institute (NCI)
• Information provided by (Responsible Party): OHSU Knight Cancer Institute

Study Description

Brief Summary:

RATIONALE: Drugs used in chemotherapy, such as treosulfan and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving treosulfan and fludarabine together with a donor bone marrow transplant or a peripheral stem cell transplant may be an effective treatment for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

PURPOSE: This phase II trial is studying giving treosulfan together with fludarabine to see how well it works in treating patients who are undergoing a donor stem cell transplant for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.

Condition or disease	Intervention/treatment	Phase
Leukemia; Myelodysplastic Syndromes	Drug: fludarabine; Drug: treosulfan; Procedure: allogeneic blood or bone marrow transplantation	Phase 1; Phase 2

Detailed Description:

OBJECTIVES:

Primary Phase

• Determine the best dose of treosulfan when administered with fludarabine as a reduced-intensity conditioning regimen followed by allogeneic hematopoietic stem cell transplantation, in terms of incidence of severe to fatal toxicity to major organ systems and incidence of graft failure, in patients with acute myeloid leukemia, lymphoblastic leukemia, or myelodysplastic syndrome.

Secondary Phase

• Determine the safety of this regimen, in terms of incidence of grade II-IV acute and chronic graft-versus-host disease, in these patients.
• Determine, preliminarily, the efficacy of this regimen, in terms of incidence of relapse, overall and disease-free survival, donor chimerism on days 28 and 100, and incidence of 200-day and 1-year nonrelapse mortality, in these patients.
• Determine the pharmacokinetic and pharmacodynamic profile of treosulfan in patients treated with this regimen.

OUTLINE: This is a multicenter, dose-finding study of treosulfan.

• Reduced-intensity conditioning: Patients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2.

Cohorts of 5-10 patients receive escalating/de-escalating doses of treosulfan until the best dose is determined among the 3 pre-selected doses. The best dose is defined as the dose preceding that at which 4 of 10 patients experience dose-limiting toxicity.

• Allogeneic hematopoietic cell transplantation (AHCT): Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0.

All male patients with acute lymphoblastic leukemia OR male patients with acute myeloid leukemia who have prior or current testicular involvement receive external-beam radiotherapy to the testicles before AHCT.

After completion of study treatment, patents are followed periodically.

PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Study of a Reduced-Intensity Conditioning Regimen With Treosulfan and Fludarabine for Allogeneic Hematopoietic Cell Transplantation for Patients With Acute Leukemia
• Study Start Date: June 2005
• Actual Primary Completion Date: October 2009
• Actual Study Completion Date: October 2009

Arms and Interventions

Intervention Details:

• Drug: fludarabine
  30 mg/m2, IV for 5 days
• Drug: treosulfan
  12 or 14 g/m2, IV for 5 days
• Procedure: allogeneic blood or bone marrow transplantation
  bone marrow or peripheral blood stem cells

Outcome Measures

Primary Outcome Measures :

1. Number of Patients Experiencing Regimen-related Toxicity Events in Study Population [ Time Frame: 34 days and 2 years ]
   Proportion of patients experiencing regimen-related toxicity to major organ systems from day minus 6 to day 28. Major organ systems: cardiac, bladder/renal, pulmonary, hepatic, neurologic and gastrointestinal
2. Number of Patients Experiencing Graft Failure [ Time Frame: 42 days ]
   Graft versus Host Disease (GVHD) is a frequent complication of allogeneic bone marrow transplant in which the engrafted donor cells attacks the patient's organs and tissue. Acute GVHD (aGVHD) usually occurs during the first three months following an allogeneic BMT. Chronic GVHD (cGVHD) usually develops after the third month post-transplant. Patients may experience one, both or neither.
3. Incidence (Percent of Participants) With Nonrelapse Mortality (NRM) by Day 200 (Secondary Phase Only) [ Time Frame: 200 days ]
   NRM (Non relapse mortality) - death not attributed to the primary cancer.

Secondary Outcome Measures :

1. Number of Subjects Who Are Without Disease at One Year as Indicator of Disease Free Survival. [ Time Frame: One year ]

Eligibility Criteria

• Ages Eligible for Study: up to 60 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of acute myeloid leukemia, lymphoblastic leukemia, or myelodysplastic syndrome

  • Any phase allowed, including any of the following:

    • Disease in remission
    • Relapsed or primary refractory disease
• No CNS leukemic involvement not clearing with prior intrathecal chemotherapy and/or cranial radiotherapy

• Planning to undergo unmanipulated allogeneic bone marrow or peripheral blood stem cell transplantation

  • Filgrastim (G-CSF) mobilization of bone marrow or stem cells allowed

• Donor available, meeting 1 of the following criteria:

  • HLA-identical related donor

  • HLA-A, -B, -C, -DRB1, and -DQB1 matched unrelated donor by high-resolution DNA typing

    • A single allele mismatch allowed

PATIENT CHARACTERISTICS:

Performance status

• Karnofsky 70-100% OR
• Lansky 70-100%

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Bilirubin ≤ 2 times upper limit of normal (ULN)
• AST ≤ 2 times ULN
• No evidence of synthetic dysfunction
• No severe cirrhosis
• No active infectious hepatitis

Renal

• Creatinine clearance ≥ 50%
• Creatinine ≤ 2 times ULN
• Dialysis independent

Cardiovascular

• No cardiac insufficiency requiring treatment
• No symptomatic coronary artery disease
• Ejection fraction ≥ 35% (for patients with history of cardiac disease or anthracycline exposure)

Pulmonary

• PO_2 ≥ 70 mm Hg AND DLCO ≥ 70% of predicted OR
• PO_2 ≥ 80 mm Hg AND DLCO ≥ 60% of predicted
• Not requiring supplementary continuous oxygen

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other disease that would severely limit life expectancy
• No HIV positivity
• No active infection requiring deferral of conditioning
• No known hypersensitivity to the study drugs

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• No prior allogeneic bone marrow or stem cell transplantation
• No concurrent umbilical cord blood or autologous transplantation

Chemotherapy

• See Disease Characteristics

Radiotherapy

• See Disease Characteristics

Other

• More than 4 weeks since prior experimental drugs
• Concurrent enrollment on another protocol for graft-versus-host disease prophylaxis allowed

Contacts and Locations

Locations

United States, Oregon

OHSU Knight Cancer Institute

Portland, Oregon, United States, 97239-3098

United States, Washington

Seattle Cancer Care Alliance

Seattle, Washington, United States, 98109-1023

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States, 98109

Sponsors and Collaborators

OHSU Knight Cancer Institute

medac GmbH

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Eneida Nemecek, MD; OHSU Knight Cancer Institute

More Information

• Responsible Party: OHSU Knight Cancer Institute
• ClinicalTrials.gov Identifier: NCT00253513
• Other Study ID Numbers: CDR0000445306; FHCRC-1931.00; MEDAC-FHCRC-1931.00; OHSU-HEM-05107-LM; 1765 ( Other Identifier: OHSU IRB )
• First Posted: November 15, 2005
• Results First Posted: February 11, 2011
• Last Update Posted: June 1, 2012
• Last Verified: February 2011

Keywords provided by OHSU Knight Cancer Institute:

adult acute lymphoblastic leukemia in remission; adult acute myeloid leukemia in remission; childhood acute lymphoblastic leukemia in remission; recurrent adult acute lymphoblastic leukemia; recurrent adult acute myeloid leukemia; recurrent childhood acute lymphoblastic leukemia; recurrent childhood acute myeloid leukemia; secondary acute myeloid leukemia; myelodysplastic syndromes; childhood myelodysplastic syndromes

Additional relevant MeSH terms:

Leukemia; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Syndrome; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Fludarabine; Treosulfan; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Alkylating; Alkylating Agents