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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Myelodysplastic Syndromes, Myeloproliferative Disorders, Leukemia, Lymphocytic, Myeloma, Lymphoma

Intervention / Treatment
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* Drug: Busulfan
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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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.)

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AUC 6000<br>Busulfan AUC Level 1: 6000 +/- 600 uM-min Fludarabine 40mg/m2 IV over 1 hour | Drug: Busulfan<br>* 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.<br>* Other names: Busulfex(R);Drug: Fludarabine<br>* Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3<br>* Other names: Fludarabine Phosphate;|
| Experimental: AUC 7500<br>Busulfan AUC Level 2: 7500 +/- 750 uM-min Fludarabine 40mg/m2 IV over 1 hour | Drug: Busulfan<br>* 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.<br>* Other names: Busulfex(R);Drug: Fludarabine<br>* Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3<br>* Other names: Fludarabine Phosphate;|
| Experimental: AUC 9000<br>AUC Level 3: 9000 +/- 900 uM-min Fludarabine 40mg/m2 IV over 1 hour | Drug: Busulfan<br>* 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.<br>* Other names: Busulfex(R);Drug: Fludarabine<br>* Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3<br>* Other names: Fludarabine Phosphate;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myeloma, Busulfan, Fludarabine, Chimerism, Allogeneic stem cell transplantation (HCT), Myelodysplastic Syndromes, Leukemia Myeloproliferative disorders (MPD), Leukemia, Lymphocytic, Lymphoma, AUC, Hematologic malignancies