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Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)

Primary Purpose

Myelodysplastic Syndromes, Myeloproliferative Disorders, Leukemia, Lymphocytic

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Busulfan
Fludarabine
Sponsored by
H. Lee Moffitt Cancer Center and Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring Busulfan, Fludarabine, Chimerism, Allogeneic stem cell transplantation (HCT), Myelodysplastic Syndromes, Leukemia Myeloproliferative disorders (MPD), Leukemia, Lymphocytic, Myeloma, Lymphoma, AUC, Hematologic malignancies

Eligibility Criteria

16 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria - Recipient: HLA A, B, C, DRB1 8/8 or 7/8 matched related or unrelated donor. HLA-DQ mismatches are not considered ie they are allowed in addition to these. Histologically confirmed diagnosis by pathologic review Diagnosis of any of the following: Acute myelogenous leukemia (AML), Acute lymphoblastic leukemia (ALL), or Non-Hodgkin's Leukemia (NHL), in first remission with high risk of relapse, refractory to primary chemotherapy, or after first relapse; acute biphenotypic or undifferentiated leukemia is also included Myelodysplastic Syndrome (MDS), with IPSS >1 Chronic myelogenous leukemia (CML), with GleevecR-refractory or intolerant chronic phase, or beyond chronic phase by morphology or cytogenetics Myeloproliferative disorders, including Ph-negative CML, myelofibrosis and chronic myelomonocytic leukemia (CMML) Multiple myeloma, refractory to two or more lines of therapy. Chronic lymphocytic leukemia (CLL), refractory to fludarabine Hodgkin's disease, refractory to primary chemotherapy or after first relapse Karnofsky performance status 70-100% Organ function: Pulmonary: Diffusing capacity of lung for carbon monoxide (DLCO) greater than 50% Cardiac: Left ventricular ejection fraction greater than 45% Renal: Creatinine clearance (measured or calculated) equal or greater than 50 ml/min Hepatic: Total bilirubin less than or equal to 2 mg/dL, (Gilbert and other syndromes with increased indirect bilirubin should be allowed); serum transaminases less than two times the upper limit of normal. Signed informed consent form in accordance with institutional policies Exclusion Criteria - Recipient: Pregnant or lactating women HIV or seropositive, confirmed by nucleic acid test (NAT) Active central nervous system (CNS) malignancy Patients with current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings) are ineligible. Unfavorable psychosocial evaluation or history of poor compliance to prescribed medical care Current use of metronidazole or acetominophen, unless medically necessary; patients must discontinue use of these agents at least 7 days prior to the start of BusulfexR administration Prior use of MylotargR (gemtuzumab ozogamicin) Prior Hematopoietic Cell Transplantation (HCT) Prior chest or abdominal irradiation with greater than 1800 cGy Presence of any of the following comorbid conditions: History of myocardial infarction or coronary artery disease requiring catheterization or stent placements less than six months prior to enrollment. All participants with history of myocardial infarction or coronary artery disease must have clearance by a cardiologist to be enrolled. Congestive heart failure (even if symptomatically controlled) Peripheral vascular disease (including intermittent claudication or history of bypass for arterial insufficiency) Untreated thoracic or abdominal aneurysm (6 cm or more) History of any cerebrovascular accident including transient ischemic attacks Dementia Connective tissue/rheumatologic disorders with active disease Diabetes uncontrolled by medication (including insulin) Hemiplegia/paraplegia History of prior malignancy (excluding nonmelanoma skin or cervical carcinoma after curative resection) less than 5 years from enrollment with the following exception. Cancer treated with curative intent less than 5 years will be reviewed on a case-by-case basis by the Principal Investigator. History of renal failure requiring renal replacement therapy (e.g., hemodialysis, peritoneal dialysis, etc.)

Sites / Locations

  • H. Lee Moffitt Cancer Center & Research Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

AUC 6000

AUC 7500

AUC 9000

Arm Description

Busulfan AUC Level 1: 6000 +/- 600 uM-min Fludarabine 40mg/m2 IV over 1 hour

Busulfan AUC Level 2: 7500 +/- 750 uM-min Fludarabine 40mg/m2 IV over 1 hour

AUC Level 3: 9000 +/- 900 uM-min Fludarabine 40mg/m2 IV over 1 hour

Outcomes

Primary Outcome Measures

Non-relapse Mortality
The number of participants dead due to causes unrelated to relapse within the first 100 days post transplant.

Secondary Outcome Measures

Severe Venous Occlusive Disease (VOD)/ Sinusoidal Obstructive Syndrome (SOS)
The number of subjects with severe VOD / SOS; severity staged according to criteria set forth by McDonald G.B., Hinds M.S., Fisher L.D., et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255-267. Assessed within the first 100 days post transplant.

Full Information

First Posted
August 3, 2006
Last Updated
January 20, 2017
Sponsor
H. Lee Moffitt Cancer Center and Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT00361140
Brief Title
Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)
Official Title
Busulfan Dose Escalation Study Based on AUC in the Setting of Busulfan/Fludarabine Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation (HCT)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2013
Overall Recruitment Status
Completed
Study Start Date
August 2005 (undefined)
Primary Completion Date
February 2012 (Actual)
Study Completion Date
February 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
H. Lee Moffitt Cancer Center and Research Institute

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Pre-transplant conditioning will include Fludarabine and dose-escalated Busulfan on days -6, -5, -4, and -3. Daily treatment doses will be adjusted to achieve target area under the plasma concentration time curve (AUC). Day 0 is the day of hematopoietic progenitor cell reinfusion. Supportive care will be based on institutional guidelines. Blood samples will be collected for dose modification based on the AUC levels. Dose escalation will proceed to determine the maximally tolerated level or AUC to evaluate the potential therapeutic benefit of higher doses of busulfan.
Detailed Description
Patients will receive anti-seizure prophylaxis beginning on day -7. Pre-transplant conditioning will include Fludarabine and dose-escalated Busulfan on days -6, -5, -4, and -3. Daily treatment doses will be adjusted to achieve target AUCs (area under the plasma concentration time curve). Day 0 is the day of hematopoietic progenitor cell reinfusion. Supportive care will be based on institutional guidelines. In an effort to prevent hepatotoxicity, ursodiol will be given to patients. During chemotherapy patients will not receive concurrent metronidazole, itraconazole, or be given acetaminophen. Blood samples will be collected at specific times after Dose 1 and Dose 4 and dose modification will be determined or based on the desired AUC levels. Doses 3 and/or 4 will be adjusted to achieve an average daily Busulfan AUC over the 4 treatment days. Dose escalation will proceed through 3 dose levels to determine the maximally tolerated level or AUC to evaluate the potential therapeutic benefit of higher doses of busulfan. Graft assessment, processing, and characterization will be done as per institutional guidelines. Donor-recipient chimerism (two genetically distinct types of blood cells) will be characterized by samples obtained pre-transplant and on days 30+/- 7, 90+/-7 and 360+/-30 post-transplant.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndromes, Myeloproliferative Disorders, Leukemia, Lymphocytic, Myeloma, Lymphoma
Keywords
Busulfan, Fludarabine, Chimerism, Allogeneic stem cell transplantation (HCT), Myelodysplastic Syndromes, Leukemia Myeloproliferative disorders (MPD), Leukemia, Lymphocytic, Myeloma, Lymphoma, AUC, Hematologic malignancies

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
72 (Actual)

8. Arms, Groups, and Interventions

Arm Title
AUC 6000
Arm Type
Experimental
Arm Description
Busulfan AUC Level 1: 6000 +/- 600 uM-min Fludarabine 40mg/m2 IV over 1 hour
Arm Title
AUC 7500
Arm Type
Experimental
Arm Description
Busulfan AUC Level 2: 7500 +/- 750 uM-min Fludarabine 40mg/m2 IV over 1 hour
Arm Title
AUC 9000
Arm Type
Experimental
Arm Description
AUC Level 3: 9000 +/- 900 uM-min Fludarabine 40mg/m2 IV over 1 hour
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
Busulfex(R)
Intervention Description
Bu IV (BusulfexR) over 3 hours on days -6, -5, -4, and -3. Day -6 and -5 doses for patients on Level 1 will be 170mg/m2. This dose is based on the dose used by DeLima (2004) adjusted proportionately to achieve an AUC of 6000uM-min. Subsequent daily doses for patients on Level 1 will be adjusted to achieve an average AUC of 6000uM-min. Day -6 and -5 doses for patients on Level 2 will be based on the mean dose required on Level 1 to achieve target AUC then adjusted proportionally for new target AUC. Subsequent daily doses will be adjusted to achieve target AUCs.
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fludarabine Phosphate
Intervention Description
Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3
Primary Outcome Measure Information:
Title
Non-relapse Mortality
Description
The number of participants dead due to causes unrelated to relapse within the first 100 days post transplant.
Time Frame
100 days
Secondary Outcome Measure Information:
Title
Severe Venous Occlusive Disease (VOD)/ Sinusoidal Obstructive Syndrome (SOS)
Description
The number of subjects with severe VOD / SOS; severity staged according to criteria set forth by McDonald G.B., Hinds M.S., Fisher L.D., et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118:255-267. Assessed within the first 100 days post transplant.
Time Frame
100 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria - Recipient: HLA A, B, C, DRB1 8/8 or 7/8 matched related or unrelated donor. HLA-DQ mismatches are not considered ie they are allowed in addition to these. Histologically confirmed diagnosis by pathologic review Diagnosis of any of the following: Acute myelogenous leukemia (AML), Acute lymphoblastic leukemia (ALL), or Non-Hodgkin's Leukemia (NHL), in first remission with high risk of relapse, refractory to primary chemotherapy, or after first relapse; acute biphenotypic or undifferentiated leukemia is also included Myelodysplastic Syndrome (MDS), with IPSS >1 Chronic myelogenous leukemia (CML), with GleevecR-refractory or intolerant chronic phase, or beyond chronic phase by morphology or cytogenetics Myeloproliferative disorders, including Ph-negative CML, myelofibrosis and chronic myelomonocytic leukemia (CMML) Multiple myeloma, refractory to two or more lines of therapy. Chronic lymphocytic leukemia (CLL), refractory to fludarabine Hodgkin's disease, refractory to primary chemotherapy or after first relapse Karnofsky performance status 70-100% Organ function: Pulmonary: Diffusing capacity of lung for carbon monoxide (DLCO) greater than 50% Cardiac: Left ventricular ejection fraction greater than 45% Renal: Creatinine clearance (measured or calculated) equal or greater than 50 ml/min Hepatic: Total bilirubin less than or equal to 2 mg/dL, (Gilbert and other syndromes with increased indirect bilirubin should be allowed); serum transaminases less than two times the upper limit of normal. Signed informed consent form in accordance with institutional policies Exclusion Criteria - Recipient: Pregnant or lactating women HIV or seropositive, confirmed by nucleic acid test (NAT) Active central nervous system (CNS) malignancy Patients with current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings) are ineligible. Unfavorable psychosocial evaluation or history of poor compliance to prescribed medical care Current use of metronidazole or acetominophen, unless medically necessary; patients must discontinue use of these agents at least 7 days prior to the start of BusulfexR administration Prior use of MylotargR (gemtuzumab ozogamicin) Prior Hematopoietic Cell Transplantation (HCT) Prior chest or abdominal irradiation with greater than 1800 cGy Presence of any of the following comorbid conditions: History of myocardial infarction or coronary artery disease requiring catheterization or stent placements less than six months prior to enrollment. All participants with history of myocardial infarction or coronary artery disease must have clearance by a cardiologist to be enrolled. Congestive heart failure (even if symptomatically controlled) Peripheral vascular disease (including intermittent claudication or history of bypass for arterial insufficiency) Untreated thoracic or abdominal aneurysm (6 cm or more) History of any cerebrovascular accident including transient ischemic attacks Dementia Connective tissue/rheumatologic disorders with active disease Diabetes uncontrolled by medication (including insulin) Hemiplegia/paraplegia History of prior malignancy (excluding nonmelanoma skin or cervical carcinoma after curative resection) less than 5 years from enrollment with the following exception. Cancer treated with curative intent less than 5 years will be reviewed on a case-by-case basis by the Principal Investigator. History of renal failure requiring renal replacement therapy (e.g., hemodialysis, peritoneal dialysis, etc.)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Teresa Field, PhD, MD
Organizational Affiliation
H. Lee Moffitt Cancer Center and Research Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Janelle Perkins, PharmD
Organizational Affiliation
H. Lee Moffitt Cancer Center and Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
H. Lee Moffitt Cancer Center & Research Institute
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22198540
Citation
Perkins JB, Kim J, Anasetti C, Fernandez HF, Perez LE, Ayala E, Kharfan-Dabaja MA, Tomblyn MR, Sullivan DM, Pidala JA, Field TL. Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012 Jul;18(7):1099-107. doi: 10.1016/j.bbmt.2011.12.584. Epub 2011 Dec 23.
Results Reference
result
Links:
URL
http://www.moffitt.org
Description
Moffitt Cancer Center Clinical Trials website

Learn more about this trial

Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)

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