Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Syndrome

Lymphoma

Leukemia

Hematologic Neoplasms

Myeloproliferative Disorders

Preleukemia

Myelodysplastic Syndromes

Leukemia, Lymphoid

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Lymphosarcoma

Chronic Myeloproliferative Disorders

Antineoplastic Agents

All Drugs and Chemicals

Fludarabine

Fludarabine phosphate

Busulfan

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Alkylating Agents

Antineoplastic Agents, Alkylating

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

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.

Fludarabine 40mg/m2 IV over 1 hour on days -6, -5, -4, and -3

Teresa Field, PhD, MD

Janelle Perkins, PharmD

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.

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.

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)

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

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.

H. Lee Moffitt Cancer Center and Research Institute

Anticipated "other than serious" Allogeneic Hematopoietic Cell Transplantation (HCT) adverse events were not tabulated.

Busulfan targeted area under the curve, level 1: 6000 +/- 600 uM-min

AUC Level 1

Busulfan targeted area under the curve, level 2: 7500 +/- 750 uM-min

AUC Level 2

Busulfan targeted area under the curve, level 3: 9000 +/- 900 uM-min

AUC Level 3

Total

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

Dr. Teresa Field

Busulfan AUC Level 1: 6000 +/- 600 uM-min Fludarabine 40 mg/m\^2 I.V. over 1 hour

AUC 6000

Busulfan AUC Level 2: 7500 +/- 750 uM-min Fludarabine 40 mg/m\^2 I.V. over 1 hour

AUC 7500

Busulfan AUC Level 3: 9000 +/- 900 uM-min Fludarabine 40 mg/m\^2 I.V. over 1 hour

AUC 9000

Severe Venous Occlusive Disease (VOD)/ Sinusoidal Obstructive Syndrome (SOS)

Sample size: dependent on dose escalation. Once the maximum tolerated dose (MTD) is reached, a total of 30 patients will be accrued to that level. If maximally tolerated AUC is level 1, a total of 30 patients will be treated on this level using tacrolimus and methotrexate as GVHD prophylaxis. This will provide 95% confidence intervals for 100-day non-relapse mortality and non-fatal toxicities with ½ widths not exceeding 0.18. Hazard ratios were calculated per the method of Gray (reference given)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)	NCT00361140	Myelodysplastic... Myeloproliferat... Leukemia, Lymph... Myeloma Lymphoma	Busulfan Fludarabine	16 Years - 65 Years	H. Lee Moffitt Cancer Center and Research Institute
Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)	NCT00361140	Myelodysplastic... Myeloproliferat... Leukemia, Lymph... Myeloma Lymphoma	Busulfan Fludarabine	16 Years - 65 Years	H. Lee Moffitt Cancer Center and Research Institute

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