Clinical trial NCT01056614: Fludarabine Phosphate, Busulfan, and Anti-Thymocyte Globulin Followed By Donor Peripheral Blood Stem Cell Transplant, Tacrolimus, and Methotrexate in Treating Patients With Myeloid Malignancies
Official title: Conditioning for Hematopoietic Cell Transplantation With Fludarabine Plus Targeted IV Busulfan and GVHD Prophylaxis With Thymoglobulin, Tacrolimus and Methotrexate in Patients With Myeloid Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Accelerated Phase Chronic Myelogenous Leukemia
Adult Acute Myeloid Leukemia in Remission
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Blastic Phase Chronic Myelogenous Leukemia
Childhood Acute Myeloid Leukemia in Remission
Childhood Chronic Myelogenous Leukemia
Childhood Myelodysplastic Syndromes
Chronic Phase Chronic Myelogenous Leukemia
de Novo Myelodysplastic Syndromes
Hematopoietic/Lymphoid Cancer
Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
Previously Treated Myelodysplastic Syndromes
Recurrent Adult Acute Myeloid Leukemia
Recurrent Childhood Acute Myeloid Leukemia
Relapsing Chronic Myelogenous Leukemia
Lead sponsor: Fred Hutchinson Cancer Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: National Cancer Institute (NCI)
First posted: 2010-01-26
Enrollment: 23
Sex: ALL
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II trial is studying the side effects and how well giving fludarabine phosphate, busulfan, anti-thymocyte globulin followed by donor peripheral blood stem cell transplant, tacrolimus, and methotrexate works in treating patients with myeloid malignancies. Giving chemotherapy, such as fludarabine phosphate and busulfan, before a donor peripheral blood 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. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving anti-thymocyte globulin before transplant and tacrolimus and methotrexate after transplant may stop this from happening.

Detailed description: PRIMARY OBJECTIVE:

I. Determine the incidence and severity of acute graft-versus-host disease (GvHD).

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics of intravenous (IV) busulfan including interdose variability and evaluation of a limited sampling strategy.

II. Determine thymoglobulin (anti-thymocyte globulin) pharmacokinetics.

III. Determine the incidence of donor engraftment.

IV. Determine system toxicities \>= grade 3 per Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 3.

V. Determine the incidence and severity of chronic GvHD.

VI. Determine the incidence of non-relapse mortality at day +100 and at 1 year (yr).

VII. Determine the incidence of relapse.

VIII. Determine relapse-free survival.

IX. Determine the incidence of Epstein-Barr virus (EBV) activation.

OUTLINE:

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -9 to -6, busulfan IV over 3 hours on days -5 to -2, and anti-thymocyte globulin IV over 6 hours on days -3 and -2 and over 4 hours on day -1. Patients undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0. Patients then receive tacrolimus IV continuously or orally (PO) every 12 hours beginning on day -1 and taper to day 180 and methotrexate IV on days 1, 3, 6, and 11.

After completion of study treatment, patients are followed at 1 year.

Eligibility criteria: Inclusion Criteria:

* Chronic myelogenous leukemia in chronic phase, accelerated phase and treated blast phase (CP2)
* Acute myeloid leukemia (AML) in remission or early relapse (\< 10% marrow blasts)
* Myelodysplastic syndromes (MDS) ( all risk groups)
* Other myeloproliferative disorders
* DONOR: related or unrelated donors matched for human leukocyte antigen (HLA)-A, B, C, DRB1, and DQB1 defined by high resolution deoxyribonucleic acid (DNA) typing or mismatched for a single HLA-A, B, C, DRB1 or DQB1 allele
* DONOR: donor must consent to peripheral blood stem cell (PBSC) mobilization with granulocyte colony-stimulating factor (G-CSF) and leukapheresis; related donors will be collected at Fred Hutchinson Cancer Research Center (FHCRC), while unrelated donors will be collected through the National Marrow Donor Program (NMDP) or other donor centers
* DONOR: Age 12-75 yrs

Exclusion Criteria:

* Cardiac insufficiency requiring treatment or symptomatic coronary artery disease
* Hepatic disease, with aspartate aminotransferase (AST) \> 2 times normal
* Severe hypoxemia, oxygen partial pressure (pO2) \< 70 mm Hg, with decreased diffusion capacity of carbon monoxide (DLCO) \< 70% of predicted; or mild hypoxemia, pO2 \< 80 mm Hg with severely decreased DLCO \< 60% of predicted
* Impaired renal function (creatinine \> 2 times normal or estimated creatinine clearance \< 60 ml/min)

  * MALE: (\[140 -age in years\] x ideal body weight \[kg\])/72 x serum creatinine (SCr) (mg/dL)
  * FEMALE: .85 x (\[140-age in years\] x ideal body weight \[kg\])/72 x SCr (mg/dL)
* Human immunodeficiency virus (HIV)-positive patients due to risk of reactivation or acceleration of HIV replication
* Female patients who are pregnant or breast feeding
* Life expectancy severely limited by diseases other than malignancy
* DONOR: donors who for any reason are unable to tolerate the mobilization and leukapheresis procedure
* DONOR: donors who are HIV-positive, or hepatitis B or C antigen-positive
* DONOR: female donors who have a positive pregnancy test

Primary outcomes:
measure: Incidence of acute GvHD
timeFrame: Day 100 post-transplant
Secondary outcomes:
measure: Pharmacokinetics of IV busulfan including interdose variability and evaluation of a limited sampling strategy
timeFrame: At 3.25, 4.5, 6, 8, 11, and 24-hours after the beginning of infusion on days -5, -4, and -3
measure: Thymoglobulin pharmacokinetics
timeFrame: On day -3 prior to the first dose, on day -1 one hour after completion of infusion and on day 1 at 0900
measure: Incidence of donor cell engraftment
timeFrame: By day 100
measure: Incidence of system toxicities >= grade 3 as graded per CTCAE v.3
timeFrame: Up to day 100 after transplantation
measure: Incidence of chronic GvHD
timeFrame: Day 100
measure: Incidence of non-relapse mortality defined as death without history of post-transplant relapse
timeFrame: At day 100
measure: Incidence of non-relapse mortality defined as death without history of post-transplant relapse
timeFrame: At 1 year
measure: Incidence of relapse
timeFrame: At 1 year
measure: Relapse-free survival
timeFrame: At 1 year
measure: Incidence of EBV activation defined as an increase in plasma EBV DNA to >= 1000 copies/mL as determined by quantitative polymerase chain reaction (PCR)
timeFrame: Up to 1 year
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
Study officials:
affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
name: H. Joachim Deeg
role: PRINCIPAL_INVESTIGATOR
References: