Fludarabine Phosphate, Busulfan, and Anti-Thymocyte Globulin Followed By Donor Peripheral Blood Stem Cell Transplant, Tacrolimus, and Methotrexate in Treating Patients With Myeloid Malignancies

Recurrent Adult Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01056614
• Other study ID #: 1913.00
• Secondary ID: NCI-2009-0178519
• Status: Active, not recruiting
• Phase: Phase 2
• First received: January 22, 2010
• Last updated: November 3, 2015
• Start date: September 2004

Study information

• Verified date: November 2015
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 23
• Est. primary completion date: August 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 60 Years

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• 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)
• Blast Crisis
• 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
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myeloid, Chronic-Phase
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
• Myeloproliferative Disorders
• Preleukemia
• Previously Treated Myelodysplastic Syndromes
• Recurrent Adult Acute Myeloid Leukemia
• Recurrent Childhood Acute Myeloid Leukemia
• Relapsing Chronic Myelogenous Leukemia
• Syndrome

Intervention

Drug:
• fludarabine phosphate
Given IV
• busulfan
Given IV

Biological:
• anti-thymocyte globulin
Given IV

Drug:
• tacrolimus
Given IV and orally
• methotrexate
Given IV

Procedure:
• peripheral blood stem cell transplantation
Undergo allogeneic PBSC transplant
• allogeneic hematopoietic stem cell transplantation
Undergo allogeneic PBSC transplant

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Research Center	National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of acute GvHD	Maximum grade of acute GVHD and the number of therapies required to treat GVHD will be determined.	Day 100 post-transplant	No
Secondary	Pharmacokinetics of IV busulfan including interdose variability and evaluation of a limited sampling strategy		At 3.25, 4.5, 6, 8, 11, and 24-hours after the beginning of infusion on days -5, -4, and -3	No
Secondary	Thymoglobulin pharmacokinetics		On day -3 prior to the first dose, on day -1 one hour after completion of infusion and on day 1 at 0900	No
Secondary	Incidence of donor cell engraftment		By day 100	No
Secondary	Incidence of system toxicities >= grade 3 as graded per CTCAE v.3		Up to day 100 after transplantation	Yes
Secondary	Incidence of chronic GvHD		Day 100	No
Secondary	Incidence of non-relapse mortality defined as death without history of post-transplant relapse		At day 100	No
Secondary	Incidence of non-relapse mortality defined as death without history of post-transplant relapse		At 1 year	No
Secondary	Incidence of relapse	Defined by either morphological or cytogenetic evidence of chronic myelogenous leukemia (CML), AML, MDS or other myeloproliferative disease in marrow, blood, or other sites, or laboratory evidence of residual disease.	At 1 year	No
Secondary	Relapse-free survival		At 1 year	No
Secondary	Incidence of EBV activation defined as an increase in plasma EBV DNA to >= 1000 copies/mL as determined by quantitative polymerase chain reaction (PCR)		Up to 1 year	No