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Treosulfan and Fludarabine Phosphate With or Without Total Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

Information source: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Acute Myeloid Leukemia in Remission; Chronic Myelomonocytic Leukemia; Minimal Residual Disease; Myelodysplastic Syndrome; Myelodysplastic/Myeloproliferative Neoplasm; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

Intervention: Allogeneic Bone Marrow Transplantation (Procedure); Fludarabine Phosphate (Drug); Laboratory Biomarker Analysis (Other); Peripheral Blood Stem Cell Transplantation (Procedure); Total-Body Irradiation (Radiation); Treosulfan (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Fred Hutchinson Cancer Research Center

Official(s) and/or principal investigator(s):
H. Joachim Deeg, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Summary

This randomized phase II trial studies how well treosulfan and fludarabine phosphate with or without total body irradiation before donor stem cell transplant works in treating patients with myelodysplastic syndrome or acute myeloid leukemia. Giving chemotherapy, such as treosulfan and fludarabine phosphate, and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus before and mycophenolate mofetil after the transplant may stop this from happening.

Clinical Details

Official title: A Randomized Phase II Multi-center Study of Treosulfan, Fludarabine and Low-Dose TBI as Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients With Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Progression free survival (PFS)

Secondary outcome:

Change in gene expression profiles

Incidence of acute GVHD, graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Incidence of chronic GVHD graded by the NCI CTCAE version 4.0

Incidence of relapse/progression

NRM

Overall Survival (OS)

Relapse risk as measured by degree of change in gene expression profiles

Detailed description: PRIMARY OBJECTIVES: I. To determine the better of two treosulfan-based conditioning regimens in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), by comparing 6-month progression-free survival. SECONDARY OBJECTIVES: I. Determine the effects of two conditioning regimens on changes in gene expression profiles, and evaluate the association of gene expression profiles and disease relapse. II. Determine the incidence of progression-free survival at 1 year and 2 years after hematopoietic cell transplantation (HCT). III. Evaluate overall survival (OS) at 6 months, at 1 year and at 2 years after HCT. IV. Determine the incidence of grades II-IV acute graft-versus-host disease (GVHD). V. Determine the incidence of chronic GVHD. VI. Determine donor chimerism around days +28 and +84. OUTLINE: Patients are randomized to 1 of 2 treatment arms. CONDITIONING REGIMEN:

ARM A: Patients receive treosulfan intravenously (IV) over 2 hours on days - 6 to -4 and

fludarabine phosphate IV over 30 minutes on days - 6 to -2.

ARM B: Patients receive treosulfan and fludarabine phosphate as in Arm A and undergo low-dose total-body irradiation (TBI) on day 0. TRANSPLANT: Patients in both arms undergo allogeneic peripheral blood stem cell (PBSC) transplant or bone marrow transplant on day 0. GVHD PROPHYLAXIS: Patients with a related donor receive tacrolimus* orally (PO) every 8 or

12 hours on days - 3 to 56 with taper to day 180. Beginning 4-6 hours after PBSC infusion,

patients also receive mycophenolate mofetil PO every 12 hours to day 28. Patients with an

unrelated donor receive tacrolimus PO every 8 or 12 hours on days - 3 to 100 with taper to

day 180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO every 8 hours to day 40 with taper to day 96. *NOTE: Patients with related donors eligible for FHCRC protocol 2545 may receive

cyclosporine IV, instead of tacrolimus, beginning on day - 3 to day 50 with a taper to day

180. After completion of study treatment, patients are followed up periodically.

Eligibility

Minimum age: N/A. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- MDS, myelodysplastic syndrome/myeloproliferative neoplasia overlap disorders

(including chronic myelomonocytic leukemia [CMML], and MDS/myeloproliferative neoplasm [MPN] unclassifiable syndromes)

- AML, other than acute promyelocytic leukemia (APL), in first or second remission or

with minimal residual disease

- With Karnofsky index or Lansky Play-Performance scale > 70% on pre-transplant

evaluation

- Able to give informed consent (if > 18 years), or with a legal guardian capable of

giving informed consent (if < 18 years)

- Patients with previous autologous or allogeneic HCT are allowed to enroll

- DONOR: Human leukocyte antigen (HLA)-identical related donors or

- DONOR: Unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 as defined by high

resolution deoxyribonucleic acid (DNA) typing; mismatch for one HLA allele is allowed

- DONOR: Donors able to undergo peripheral blood stem cell collection or bone marrow

harvest

- DONOR: Donors in good general health, with a Karnofsky or Lansky play performance

score > 90%

- DONOR: Donors able to give informed consent (if > 18 years), or with a legal guardian

capable of giving informed consent (if < 18 years) Exclusion Criteria:

- Receiving umbilical cord blood

- With impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable

to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist

- With impaired pulmonary function as evidenced by partial pressure of oxygen (pO2) <

70 mm Hg and diffusing capacity of the lungs for carbon monoxide (DLCO) < 70% of predicted or pO2 < 80 mm Hg and DLCO < 60% of predicted; or receiving supplementary continuous oxygen

- With impaired renal function as evidenced by creatinine-clearance < 50% for age,

weight, height or serum creatinine > 2 x upper limit of normal or dialysis-dependent

- With hepatic dysfunction as evidenced by total bilirubin > 2. 0 x upper limit of

normal or evidence of synthetic dysfunction or severe cirrhosis

- With hepatic dysfunction as evidenced by aspartate aminotransferase (AST) > 2. 0 x

upper limit of normal or evidence of synthetic dysfunction or severe cirrhosis

- With active infectious disease requiring deferral of conditioning, as recommended by

an infectious disease specialist

- With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis

- With central nervous system (CNS) leukemic involvement not clearing with intrathecal

chemotherapy, cranial irradiation or both prior to initiating conditioning (day - 6)

- Any other malignancy, excluding basal or squamous cell carcinoma of the skin,

cervical carcinoma in situ, localized prostate cancer, or superficial bladder cancer stage 0, from which the subject has not been disease-free for at least 3 years

- With life expectancy severely limited by diseases other than malignancy

- Women who are pregnant or lactating

- With known hypersensitivity to treosulfan or fludarabine (fludarabine phosphate)

- Receiving another experimental drug within 4 weeks before initiation of conditioning

(day - 6)

- Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18

years) unable to give informed consent

- DONOR: Individuals deemed unable to undergo marrow harvesting or PBSC mobilization

and leukapheresis

- DONOR: Individuals who are HIV-positive

- DONOR: Individuals with active infectious hepatitis

- DONOR: Females with a positive pregnancy test

- DONOR: Persons unable to give informed consent (if > 18 years) or with a legal

guardian (if < 18 years) unable to give informed consent

Locations and Contacts

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, Seattle, Washington 98109, United States; Recruiting
H. Joachim Deeg, Phone: 206-667-5985
H. Joachim Deeg, Principal Investigator
Additional Information

Starting date: November 2013
Last updated: May 14, 2015

Page last updated: August 20, 2015

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