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

May 24, 2012 updated by: OHSU Knight Cancer Institute

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

Phase

Phase 2
Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

United States
- Oregon
  - Portland, Oregon, United States, 97239-3098
    - OHSU Knight Cancer Institute
- Washington
  - Seattle, Washington, United States, 98109
    - Fred Hutchinson Cancer Research Center
  - Seattle, Washington, United States, 98109-1023
    - Seattle Cancer Care Alliance

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 60 years (Child, Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Interventional Model: Single Group Assignment
Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	34 days and 2 years
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.	42 days
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.	200 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of Subjects Who Are Without Disease at One Year as Indicator of Disease Free Survival. Time Frame: One year	One year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

OHSU Knight Cancer Institute

Collaborators

National Cancer Institute (NCI)

medac GmbH

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2005

Primary Completion (Actual)

October 1, 2009

Study Completion (Actual)

October 1, 2009

Study Registration Dates

First Submitted

November 11, 2005

First Submitted That Met QC Criteria