Clinical trial NCT00253513: 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
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia
Myelodysplastic Syndromes
Keywords: 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
Lead sponsor: OHSU Knight Cancer Institute
Sponsor class: OTHER
Collaborators: name: medac GmbH
name: National Cancer Institute (NCI)
First posted: 2005-11-15
Enrollment: 60
Sex: ALL
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Number of Patients Experiencing Regimen-related Toxicity Events in Study Population
timeFrame: 34 days and 2 years
measure: Number of Patients Experiencing Graft Failure
timeFrame: 42 days
measure: Incidence (Percent of Participants) With Nonrelapse Mortality (NRM) by Day 200 (Secondary Phase Only)
timeFrame: 200 days
Secondary outcomes:
measure: Number of Subjects Who Are Without Disease at One Year as Indicator of Disease Free Survival.
timeFrame: One year
Other outcomes:
Locations:
city: Portland
country: United States
facility: OHSU Knight Cancer Institute
state: Oregon
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: OHSU Knight Cancer Institute
name: Eneida Nemecek, MD
role: PRINCIPAL_INVESTIGATOR
References: