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

• Sponsor: OHSU Knight Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00253513
• Collaborator: medac GmbH (Industry), National Cancer Institute (NCI) (NIH)
• Enrollment: 60
• Locations: 3
• Duration (Months): 52
• Patients Per Site: 20
• Patients Per Site Per Month: 0.4

Study Details

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
• 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: Jun 1, 2005
• Actual Primary Completion Date: Oct 1, 2009
• Actual Study Completion Date: Oct 1, 2009

Outcome Measures

Primary Outcome Measures

1. Number of Patients Experiencing Regimen-related Toxicity Events in Study Population [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 [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) [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. [One year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	OHSU Knight Cancer Institute	Portland	Oregon	United States	97239-3098
2	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109-1023
3	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• 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
• First Posted: Nov 15, 2005
• Last Update Posted: Jun 1, 2012
• Last Verified: Feb 1, 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; Fludarabine; Treosulfan

Study Results

Participant Flow

Recruitment Details	Patients recruited at OHSU Knight Cancer Institute clinics in Portland, Oregon and Fred Hutchinson Cancer Research Center or University of Washington Medical Center clinics, Seattle, Washington.

Arm/Group Title	Treosulfan and Fludarabine Conditioning
Arm/Group Description	Conditioning with Treosulfan (12 or 14 g/m2, IV for 5 days) and Fludarabine (30 mg/m2, IV for 5 days) followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies
Period Title: Overall Study
STARTED	60
COMPLETED	60
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treosulfan and Fludarabine Conditioning
Arm/Group Description	Conditioning with Treosulfan (12 or 14 g/m2, IV for 5 days) and Fludarabine (30 mg/m2, IV for 5 days) followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies
Overall Participants	60
Age, Customized (Number) [Number]
< 21 years	10 16.7%
Between 21 - 50 years	31 51.7%
Between 50 - 60 years	19 31.7%
Sex: Female, Male (Count of Participants)
Female	36 60%
Male	24 40%
Region of Enrollment (participants) [Number]
United States	60 100%
Disease status at transplantation (Number) [Number]
Acute Lymphoblastic Leukemia(ALL)2nd/3rd remission	3 5%
Acute Myelogenous Leukemia(AML)1st remission	26 43.3%
AML, 2nd or greater remission.	10 16.7%
AML, relapsed or primary refractory	8 13.3%
Myelodysplastic Syndrome(MDS): Refract. Anemia(RA)	6 10%
MDS: RA with excess blasts in transformation	7 11.7%
Disease risk group (Number) [Number]
Low - AML/ALL in 1st rem., MDS with IPSS=0	26 43.3%
Standard (ALL or AML in 2nd or greater rem.)	22 36.7%
High -relapsed/refract. ALL/AML/MDS w/ IPSS>=2.5	12 20%
Cytogenetic risk group (Number) [Number]
Good	16 26.7%
Intermediate	8 13.3%
Poor	36 60%
Hematopoietic Cell Transplantation Comorbidity Index (HCT CI) (Number) [Number]
0	13 21.7%
1-2	19 31.7%
>=3	28 46.7%
Donor type (participants) [Number]
HLA (human leukocyte antigen) -identical sibling	30 50%
HLA-matched unrelated donor	30 50%
Stem cell source (participants) [Number]
Bone marrow	7 11.7%
Filgrastim-mobilized PBPC	53 88.3%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Experiencing Regimen-related Toxicity Events in Study Population
Description	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
Time Frame	34 days and 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treosulfan and Fludarabine Conditioning
Arm/Group Description	Conditioning with Treosulfan (12 or 14 g/m2, IV for 5 days) and Fludarabine (30 mg/m2, IV for 5 days) followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies
Measure Participants	60
Severe Regimen Related Toxicity (RRT)	2 3.3%
Nonrelapse mortality at 2 years	5 8.3%

2. Primary Outcome

Title	Number of Patients Experiencing Graft Failure
Description	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.
Time Frame	42 days

Outcome Measure Data

Analysis Population Description

For graft failure 2 of the 60 patients were not evaluable because they exeperienced another event (relapsed) before they could be evaluable for graft failure.

Arm/Group Title	Treosulfan and Fludarabine Conditioning
Arm/Group Description	Conditioning with Treosulfan (12 or 14 g/m2, IV for 5 days) and Fludarabine (30 mg/m2, IV for 5 days) followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies
Measure Participants	58
acute graft vs. host disease (aGVHD)	36 60%
chronic graft vs. host disease (cGVHD)	31 51.7%

3. Primary Outcome

Title	Incidence (Percent of Participants) With Nonrelapse Mortality (NRM) by Day 200 (Secondary Phase Only)
Description	NRM (Non relapse mortality) - death not attributed to the primary cancer.
Time Frame	200 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treosulfan and Fludarabine Conditioning
Arm/Group Description	Conditioning with Treosulfan (12 or 14 g/m2, IV for 5 days) and Fludarabine (30 mg/m2, IV for 5 days) followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies
Measure Participants	60
Number (95% Confidence Interval) [percent of participants]	5 8.3%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treosulfan and Fludarabine Conditioning
Arm/Group Description	Conditioning with Treosulfan (12 or 14 g/m2, IV for 5 days) and Fludarabine (30 mg/m2, IV for 5 days) followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies
Measure Participants	60
Number [participants]	58 96.7%

Adverse Events

Arm/Group Title	Treosulfan and Fludarabine Conditioning
Arm/Group Description	Conditioning with Treosulfan (12 or 14 g/m2, IV for 5 days) and Fludarabine (30 mg/m2, IV for 5 days) followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies
All Cause Mortality
	Treosulfan and Fludarabine Conditioning
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treosulfan and Fludarabine Conditioning
	Affected / at Risk (%)	# Events
Total	5/60 (8.3%)
Blood and lymphatic system disorders
Death - intracranial hemmorrage	1/60 (1.7%)	1
Immune system disorders
Death - cGVHD	2/60 (3.3%)	2
Infections and infestations
Death - fungal infection	2/60 (3.3%)	2
Respiratory, thoracic and mediastinal disorders
Grade 4 mucositis	1/60 (1.7%)	1
Other (Not Including Serious) Adverse Events
	Treosulfan and Fludarabine Conditioning
	Affected / at Risk (%)	# Events
Total	0/60 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.