Allogeneic Hematopoietic Cell Transplantation for Patients With Busulfex-based Regimen

NCT ID: NCT00448357

Last Updated: 2017-07-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 54 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-10-31
• Study Completion Date: 2015-11-30

Brief Summary

RATIONALE: Giving chemotherapy, such as fludarabine and busulfan, before a donor peripheral stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps 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 a monoclonal antibody, alemtuzumab, before the transplant and tacrolimus after the transplant may stop this from happening.

PURPOSE: The phase I portion of this trial identified the maximum tolerated dose of busulfan after treating 40 patients on a dose-escalation scheme. We are now treating an additional 26 patients on the phase II portion of the trial at a Pharmacokinetic (PK)-directed dose of total area under curve (AUC) 6912 micrometer (uM)-min/24 hours. We transitioned to the Phase II portion of the study in October 2009.

Detailed Description

OBJECTIVES:

Primary

• Phase I Objective: To identify the maximum tolerated dose of continuous infusion IV busulfan based on blood levels derived from a test dose in conjunction with fludarabine, ATG and methotrexate plus tacrolimus for GVHD prophylaxis
• Phase II Objective: To determine the one-year disease-free survival (DFS) rate at the maximum tolerated dose identified during Phase I of the trial (target AUC 6912)

Secondary

• Determine the overall and disease-free survival of patients treated with this regimen.
• Determine the dose-limiting toxicities of this regimen in these patients.
• Determine the capacity of test dosing of busulfan that would result in the desired area under the curve concentration exposure of patients receiving a full-dose busulfan regimen.
• Determine the incidence of graft-vs-host disease and DNA chimerism between 1 month and 2 years post-transplantation in these patients.
• Compare the overall survival (OS) and disease-free survival (DFS) rates for patients treated with Campath vs. patients treated with ATG/Methotrexate for GVHD control

OUTLINE: This is a non-randomized, open-label, parallel group study of busulfan. Patients are stratified according to donor relationship - matched related donor (MRD) vs matched unrelated donor (MUD).

• Conditioning regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours once within days -15 to -10 and then IV continuously over 90 hours on days -7 to -4. Patients with a MRD also receive Methotrexate (MTX) on Days +1, +3, and +6. Patients with a MUD receive ATG on Days -3 and -2 and MTX on Days +1, +3 and +6.

Phase I portion only: Cohorts of 3-6 patients receive escalating doses of busulfan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Allogeneic peripheral blood stem cell transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously beginning on day 5 and continuing until blood counts recover.
• Graft-vs-host disease (GVHD) prophylaxis: Patients receive oral tacrolimus twice daily on days -1 to 180 or days -1 to 240.
• Donor lymphocyte infusion (DLI): Patients who do not achieve CR, do not have GVHD, and have been off immunosuppressants for at least 30 days may receive up to 3 DLIs, at least 8 weeks apart, after completion of tacrolimus.

After the completion of study treatment, patients are followed periodically for up to 5 years.

Conditions

Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

GVHD prophylaxis

Subjects with matched-related donors (MRDs) were treated with tacrolimus and methotrexate with or without alemtuzumab for graft vs host disease prophylaxis Subjects also receive busulfan and fludarabine .

Matched unrelated donor (MUD) or mismatched related donor (MMRD) subjects receive GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) + Methotrexate Subjects also receive busulfan, fludarabine, and tacrolimus.

Group Type: EXPERIMENTAL

rabbit anti-thymocyte globulin (ATG)

Intervention Type: BIOLOGICAL

.5 mg/kg on day -3 and 2.5 mg/kg on day -2

therapeutic allogeneic lymphocytes

Intervention Type: BIOLOGICAL

minimum total cluster of differentiation (CD34+) cells of 3 x 10\^6 cells/kg and a maximum of 8 x 10\^6 cells/kg will be infused on day 0

busulfan

Intervention Type: DRUG

PK-targeted continuous IV infusion over 90 hours on Days -7 to -4.

fludarabine phosphate

Intervention Type: DRUG

30 mg/m\^2/day x 5 days intravenous piggyback (IVPB) over 30 minutes on Days -7 through -3

tacrolimus

Intervention Type: DRUG

The suggested starting dose is 0.03 mg/kg po bid starting on day -1

allogeneic hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

A minimum total CD34+ cell dose of 3 x 10\^6 cells/kg and maximum of 8 x 10\^6 cells/kg will be infused on day 0

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

minimum total CD34+ cell dose of 3 x 10\^6 cells/kg and a maximum of 8 x 10\^6 cells/kg will be infused on day 0

methotrexate

Intervention Type: DRUG

5 mg/m\^2 on days +1, +3 and +6

Interventions

rabbit anti-thymocyte globulin (ATG)

.5 mg/kg on day -3 and 2.5 mg/kg on day -2

Intervention Type: BIOLOGICAL

therapeutic allogeneic lymphocytes

minimum total cluster of differentiation (CD34+) cells of 3 x 10\^6 cells/kg and a maximum of 8 x 10\^6 cells/kg will be infused on day 0

Intervention Type: BIOLOGICAL

busulfan

PK-targeted continuous IV infusion over 90 hours on Days -7 to -4.

Intervention Type: DRUG

fludarabine phosphate

30 mg/m\^2/day x 5 days intravenous piggyback (IVPB) over 30 minutes on Days -7 through -3

Intervention Type: DRUG

tacrolimus

The suggested starting dose is 0.03 mg/kg po bid starting on day -1

Intervention Type: DRUG

allogeneic hematopoietic stem cell transplantation

A minimum total CD34+ cell dose of 3 x 10\^6 cells/kg and maximum of 8 x 10\^6 cells/kg will be infused on day 0

Intervention Type: PROCEDURE

peripheral blood stem cell transplantation

minimum total CD34+ cell dose of 3 x 10\^6 cells/kg and a maximum of 8 x 10\^6 cells/kg will be infused on day 0

Intervention Type: PROCEDURE

methotrexate

5 mg/m\^2 on days +1, +3 and +6

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Histologically confirmed diagnosis of any of the following:

Chronic lymphocytic leukemia or prolymphocytic leukemia Chemotherapy-refractory or advanced disease after ≥ 3 prior treatments Chronic myelogenous leukemia Diagnosis based on t(9;22) or related t(9;12) cytogenetic abnormalities AND characterized by elevated white blood counts (WBC) in peripheral blood or marrow Patients with progressive disease on imatinib mesylate or other protein tyrosine kinase inhibitors; less than a major cytogenetic or fluorescent in situ hybridization (FISH) complete response (CR) after a minimum of 6 months of targeted therapy; or less than a complete FISH or cytogenetic response after 12 months of targeted therapy are eligible Patients with other cytogenetic abnormalities, such as t(9;12), that are associated with an aggressive clinical course are eligible Non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma Any World Health Organization (WHO) classification histologic subtype allowed Must have advanced disease as defined by relapse after initial CR or failure to achieve CR OR deemed to have less than a 30% likelihood of durable response with an autologous stem cell transplant Refractory low-grade NHL histologies or any intermediate or aggressive large cell or mantle cell lymphoma allowed Acute myeloid leukemia (AML) High-risk disease in first CR (CR1) OR evidence of any recurrent disease beyond CR1 High-risk individuals are those requiring more than 1 course of induction therapy to achieve remission; those with extra-medullary disease at presentation; or those with high-risk cytogenetic abnormalities (abnormalities of chromosomes 5, 7, 2, trisomy 8, or 3) or > 2 cytogenetic abnormalities

• Multiple myeloma
• Myelodysplastic syndromes (MDS) Must have MDS defined by WHO criteria with > 5% blasts or high-risk cytogenetic abnormalities (abnormalities of chromosomes 5, 7, 2, trisomy 8, or 3)
• Acute lymphoblastic leukemia (ALL) High-risk disease in CR1 OR beyond CR1 High-risk disease includes the following: t(9;22) or t(4;11); WBC > 30,000/mm³ at presentation; non-T-cell phenotype; or more than 30 years of age
• Myelofibrosis/agnogenic myeloid metaplasia

• Patients must be transfusion dependant or have evidence of evolving AML as evidenced by an excess of blasts or a state of marrow failure/fibrosis
• Myeloproliferative disorders with advanced disease (e.g., progressive or spent phase polycythemia vera, myelofibrosis, or essential thrombocythemia)

• Any of the following categories of donors are acceptable*:
• Human Leucocyte Antigen (HLA)-identical or 1 antigen-mismatched sibling (5/6, 6/6, or 8/10) donor

• Minimal serologic typing required for class I (A, B); molecular typing required for class II (DRB1)
• 8/10 matched unrelated donor (MUD)

• Molecular analysis at HLA-A, -B, -C, -DRB1 and -DQB1 (8/10 match) by high resolution typing is required
• 5/6 MUD

• Molecular analysis at HLA-A, -B, and -DRB1 required Note: *No syngeneic donors

PATIENT CHARACTERISTICS:

• Performance status 0-2
• Bilirubin ≤ 2 times upper limit of normal (ULN)
• Aspartate aminotransferase (AST) ≤ 2 times ULN
• Creatinine clearance ≥ 50 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Diffusing capacity of the lungs for carbon monoxide (DLCO) > 60% with no symptomatic pulmonary disease
• Left ventricular ejection fraction (LVEF) ≥ 50% by multigated acquisition (MUGA) scan

Exclusion Criteria

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 4 weeks since prior chemotherapy, radiotherapy, or surgery

• Cranial radiotherapy or intrathecal therapy as prophylaxis against central nervous system (CNS) recurrence within the past 4 weeks allowed (in high-risk patients)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Otsuka America Pharmaceutical

INDUSTRY

Sponsor Role: collaborator

UNC Lineberger Comprehensive Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Thomas C. Shea, MD

Role: PRINCIPAL_INVESTIGATOR

UNC Lineberger Comprehensive Cancer Center

Locations

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, United States

Countries

United States

References

Shea TC, Walko C, Chung Y, Ivanova A, Sheets J, Rao K, Gabriel D, Comeau T, Wood W, Coghill J, Armistead P, Sarantopoulos S, Serody J. Phase I/II Trial of Dose-Escalated Busulfan Delivered by Prolonged Continuous Infusion in Allogeneic Transplant Patients. Biol Blood Marrow Transplant. 2015 Dec;21(12):2129-2135. doi: 10.1016/j.bbmt.2015.07.016. Epub 2015 Jul 22.

Reference Type: RESULT

PMID: 26210442 (View on PubMed)

Related Links

http://unclineberger.org

University of North Carolina Lineberger Comprehensive Cancer Center

Other Identifiers

P30CA016086

Identifier Type: NIH

Identifier Source: secondary_id

View Link

LCCC 0510

Identifier Type: -

Identifier Source: org_study_id

NCT00618306

Identifier Type: -

Identifier Source: nct_alias