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

Leukemia Clinical Trial

Official title:

A Study of a Reduced-Intensity Conditioning Regimen With Treosulfan and Fludarabine for Allogeneic Hematopoietic Cell Transplantation for Patients With Acute Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00253513
• Other study ID #: CDR0000445306
• Secondary ID: FHCRC-1931.00MED
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: November 11, 2005
• Last updated: May 24, 2012
• Start date: June 2005
• Est. completion date: October 2009

Study information

• Verified date: February 2011
• Source: OHSU Knight Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: October 2009
• Est. primary completion date: October 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 60 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia
• Syndrome

Intervention

Drug:
• fludarabine
30 mg/m2, IV for 5 days
• treosulfan
12 or 14 g/m2, IV for 5 days

Procedure:
• allogeneic blood or bone marrow transplantation
bone marrow or peripheral blood stem cells

Locations

Country	Name	City	State
United States	OHSU Knight Cancer Institute	Portland	Oregon
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
OHSU Knight Cancer Institute	medac GmbH, National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Patients Experiencing Regimen-related Toxicity Events in Study Population	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	34 days and 2 years	Yes
Primary	Number of Patients Experiencing Graft Failure	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.	42 days	Yes
Primary	Incidence (Percent of Participants) With Nonrelapse Mortality (NRM) by Day 200 (Secondary Phase Only)	NRM (Non relapse mortality) - death not attributed to the primary cancer.	200 days	Yes
Secondary	Number of Subjects Who Are Without Disease at One Year as Indicator of Disease Free Survival.		One year	No