Fludarabine and PK-Directed Busulfan With or Without ATG Followed By Donor Peripheral Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Diseases

Lymphoma Clinical Trial

— LCCC 0510  

Official title:

Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Undergoing Dose-Adjusted Treatment With A Maximally Intensive Busulfex-Based Therapeutic Regimen

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00448357
• Other study ID #: LCCC 0510
• Secondary ID: P30CA016086CDR00
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• First received: March 14, 2007
• Last updated: November 23, 2015
• Start date: October 2005
• Est. completion date: August 2017

Study information

• Verified date: November 2015
• Source: UNC Lineberger Comprehensive Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review BoardUnited States: Federal Government
• Study type: Interventional

Clinical Trial 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 PK-directed dose of total AUC 6912 uM-min/24 hours. We transitioned to the Phase II portion of the study in October 2009.

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.

Other known NCT identifiers

• NCT00618306

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 60
• Est. completion date: August 2017
• Est. primary completion date: November 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

DISEASE CHARACTERISTICS:

• 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 WBC counts 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 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*:

• 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)

• AST = 2 times ULN

• Creatinine clearance = 50 mL/min

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• DLCO > 60% with no symptomatic pulmonary disease

• LVEF = 50% by MUGA

• No uncontrolled or severe cardiovascular disease, pulmonary disease, or infection that, in the opinion of the treating physician, would make this study unreasonably hazardous to the patient

• No other serious illness that would limit survival to < 2 years

• No psychiatric condition that would preclude study compliance

• No uncontrolled diabetes mellitus or active serious infection

• No active second malignancy except for nonmelanomatous skin cancer

• No known hypersensitivity to E. coli-derived products

• No HIV positivity

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

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

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Myeloproliferative Disorders
• Leukemia
• Lymphoma
• Multiple Myeloma
• Multiple Myeloma and Plasma Cell Neoplasm
• Myelodysplastic Syndromes
• Myeloproliferative Disorders
• Neoplasms, Plasma Cell
• Plasmacytoma
• Preleukemia

Intervention

Biological:
• rabbit anti-thymocyte globulin
.5 mg/kg on day -3 and 2.5 mg/kg on day -2
• therapeutic allogeneic lymphocytes
minimum total 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

Drug:
• busulfan
PK-targeted continuous IV infusion over 90 hours on Days -7 to -4.
• fludarabine phosphate
30 mg/m^2/day x 5 days IVPB over 30 minutes on Days -7 through -3
• tacrolimus
The suggested starting dose is 0.03 mg/kg po bid starting on day -1

Procedure:
• 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
• 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

Drug:
• methotrexate
5 mg/m^2 on days +1, +3 and +6

Locations

Country	Name	City	State
United States	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
UNC Lineberger Comprehensive Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	One-year disease-free survival (DFS) rate at the maximum tolerated dose identified during phase I of the trial (target AUC 6912)		One year post-transplant	No
Secondary	Overall and disease-free survival		Five years post-transplant	No
Secondary	Dose-limiting toxicities of busulfan		6 weeks post-transplant	Yes
Secondary	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		Day -15 to Day -11	No
Secondary	To assess the incidence of graft vs host disease and DNA chimerism in patients between one month and two years post transplant		1 Month to 2 Years post-transplant	No