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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT00361140
First received: August 3, 2006
Last updated: April 24, 2013
Last verified: June 2013
  Purpose

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. 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.


Condition Intervention Phase
Myelodysplastic Syndromes
Myeloproliferative Disorders
Leukemia, Lymphocytic
Myeloma
Lymphoma
Drug: Busulfan
Drug: Fludarabine
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Busulfan Dose Escalation Study Based on AUC in the Setting of Busulfan/Fludarabine Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation (HCT)

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • Non-relapse Mortality [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
    The number of subjects 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) [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]

    The number of subjects with severe VOD / SOS; severity staged according to criteria set forth by McDonald GB, Hinds MS, Fisher LD, 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



Enrollment: 72
Study Start Date: August 2005
Study Completion Date: February 2012
Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AUC 6000

Busulfan AUC Level 1: 6000 +/- 600 uM-min

Fludarabine 40mg/m2 IV over 1 hour

Drug: Busulfan

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.

Other Name: Busulfex(R)
Drug: Fludarabine
Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3
Other Name: Fludarabine Phosphate
Experimental: AUC 7500

Busulfan AUC Level 2: 7500 +/- 750 uM-min

Fludarabine 40mg/m2 IV over 1 hour

Drug: Busulfan

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.

Other Name: Busulfex(R)
Drug: Fludarabine
Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3
Other Name: Fludarabine Phosphate
Experimental: AUC 9000

AUC Level 3: 9000 +/- 900 uM-min

Fludarabine 40mg/m2 IV over 1 hour

Drug: Busulfan

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.

Other Name: Busulfex(R)
Drug: Fludarabine
Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3
Other Name: Fludarabine Phosphate

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.

  Eligibility

Ages Eligible for Study:   16 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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:

    1. AML, ALL, or 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
    2. MDS, with IPSS >1
    3. CML, with GleevecR-refractory or intolerant chronic phase, or beyond chronic phase by morphology or cytogenetics
    4. Myeloproliferative disorders, including Ph-negative CML, myelofibrosis and chronic myelomonocytic leukemia (CMML)
    5. Multiple myeloma, refractory to two or more lines of therapy.
    6. CLL, refractory to fludarabine
    7. Hodgkin's disease, refractory to primary chemotherapy or after first relapse
    8. Karnofsky performance status 70-100%
  • Organ function:

    1. Pulmonary: DLCO greater than 50%
    2. Cardiac: left ventricular ejection fraction greater than 45%
    3. Renal: creatinine clearance (measured or calculated) equal or greater than 50 ml/min
    4. Hepatic: total bilirubin less than or equal to 2mg/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 NAT
  • Active 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 HCT
  • Prior chest or abdominal irradiation with greater than 1800 cGy
  • Presence of any of the following comorbid conditions:

    1. History of myocardial infarction or coronary artery disease requiring catheterization or stent placements less than six months prior to enrollment. All subjects with history of myocardial infarction or coronary artery disease must have clearance by a cardiologist to be enrolled
    2. Congestive heart failure (even if symptomatically controlled)
    3. Peripheral vascular disease (including intermittent claudication or history of bypass for arterial insufficiency)
    4. Untreated thoracic or abdominal aneurysm (6cm or more)
    5. History of any cerebrovascular accident including transient ischemic attacks
    6. Dementia
    7. Connective tissue/rheumatologic disorders with active disease
    8. Diabetes uncontrolled by medication (including insulin)
    9. Hemiplegia/paraplegia
    10. 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.
    11. History of renal failure requiring renal replacement therapy (e.g., hemodialysis, peritoneal dialysis, etc)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00361140

Locations
United States, Florida
H. Lee Moffitt Cancer Center & Research Institute
Tampa, Florida, United States, 33612
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
Investigators
Principal Investigator: Teresa Field, PhD, MD H. Lee Moffitt Cancer Center and Research Institute
Principal Investigator: Janelle Perkins, PharmD H. Lee Moffitt Cancer Center and Research Institute
  More Information

Additional Information:
Publications:
Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT00361140     History of Changes
Other Study ID Numbers: MCC-14178
Study First Received: August 3, 2006
Results First Received: January 30, 2013
Last Updated: April 24, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
Busulfan
Fludarabine
Chimerism
Allogeneic stem cell transplantation (HCT)
Myelodysplastic Syndromes
Leukemia Myeloproliferative disorders (MPD)
Leukemia, Lymphocytic
Myeloma
Lymphoma
AUC
Hematologic malignancies

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Lymphoma
Multiple Myeloma
Neoplasms, Plasma Cell
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Precancerous Conditions
Busulfan
Fludarabine monophosphate
Fludarabine
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 20, 2014