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

Busulfan Dose Escalation Study Based on AUC in the Setting of Busulfan/Fludarabine Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation (HCT)

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Myelodysplastic Syndromes; Myeloproliferative Disorders; Myeloma; Leukemia, Lymphocytic
• Intervention / Treatment: Drug: Busulfan; Drug: Fludarabine

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.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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. 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
  2. Myelodysplastic Syndrome (MDS), with IPSS >1
  3. Chronic myelogenous leukemia (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. Chronic lymphocytic leukemia (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: Diffusing capacity of lung for carbon monoxide (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 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:

  1. 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.
  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 (6 cm 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.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: Busulfex(R); Drug: Fludarabine; Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3; Other Names: 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 Names: Busulfex(R); Drug: Fludarabine; Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3; Other Names: 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 Names: Busulfex(R); Drug: Fludarabine; Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3; Other Names: Fludarabine Phosphate

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	100 days

Collaborators and Investigators

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Investigators: Principal Investigator: Janelle Perkins, PharmD, H. Lee Moffitt Cancer Center and Research Institute; Principal Investigator: Teresa Field, PhD, MD, H. Lee Moffitt Cancer Center and Research Institute

Publications and helpful links

General Publications

• 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.

Helpful Links

• Moffitt Cancer Center Clinical Trials Website

Study record dates

Study Major Dates

• Study Start: August 1, 2005
• Primary Completion (Actual): February 1, 2012
• Study Completion (Actual): February 1, 2012

Study Registration Dates

• First Submitted: August 3, 2006
• First Submitted That Met QC Criteria: August 3, 2006
• First Posted (Estimate): August 7, 2006

Study Record Updates

• Last Update Posted (Actual): March 3, 2017
• Last Update Submitted That Met QC Criteria: January 20, 2017
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: Lymphoma; Myelodysplastic Syndromes; Myeloma; Fludarabine; Hematologic malignancies; Busulfan; Chimerism; AUC; Allogeneic stem cell transplantation (HCT); Leukemia Myeloproliferative disorders (MPD); Leukemia, Lymphocytic
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Preleukemia; Leukemia, Lymphoid; Myeloproliferative Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Fludarabine; Fludarabine phosphate; Busulfan
• Other Study ID Numbers: MCC-14178