Targeted, Dose-Escalation Busulfan-Etoposide as Prep Regimen
Busulfan and etoposide have been used as preparative therapy for autoSCT (stem cell transplant) in adults with acute myeloid leukemia (AML) at UCSF for the past 10 years. Over this period and together with collaborative transplant centers, over 200 patients have received this treatment. By intent-to-treat analysis, and with median follow-up of 7.0 years, the 5-year DFS is 55%. The current protocol will utilize the combination of IV Busulfan (BU) and etoposide. The busulfan dose will be escalated amongst 3 targeted dose levels. All targeted dose levels represent higher busulfan dosing than standard myeloablative dosing, with the lowest dose being approximately 14% higher than standard. Busulfan levels will be monitored after the first, fourth and twelfth doses. Dose adjustments will be made "in real time" based on AUC levels determined from the first and fourth doses. This strategy of busulfan monitoring and dose adjustment has improved the therapeutic widow of BU in previous clinical trials.
The current protocol will utilize the combination of intravenous busulfan and etoposide. The busulfan dose will be escalated amongst 3 targeted dose levels (area under the curve (AUC) levels at time 6 hours of 1250 uMol*min, 1400 uMol*min and 1550 uMol*min). All targeted dose levels represent higher busulfan dosing than standard myeloablative dosing with the lowest dose (1250 uMol*min) being approximately 14% higher than standard. In the absence of dose-limiting toxicity, cohorts of 4-6 patients will be treated at each dose level and 10 additional patients will be treated at the maximum tolerated dose (MTD) to confirm safety. The busulfan dosing will begin at 1 mg/kg based on historical plasma levels obtained from patients receiving BU at a starting dose of 0.8 mg/kg at UCSF Medical Center.
The highest dose level proposed for this study will exceed the reported toxic level for busulfan in the alloSCT setting. Patients will be followed closely for toxicity and strict stopping rules have been included. Eligibility criteria will exclude patients with prior history of hepatotoxicity or viral hepatitis. Potential hepatotoxic agents will not be allowed just prior to and during the busulfan dosing period. In addition, patients who experience hepatotoxicty during pre-transplant mobilization therapy may be excluded from receiving dose-escalated busulfan therapy. Every attempt will be made to prevent or avoid hepatotoxicity.
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study of Targeted, Dose-Escalated Intravenous Busulfan and Bolus Etoposide as Preparative Therapy for Patients With Acute Myeloid Leukemia Undergoing Autologous Stem Cell Transplantation|
- to determine MTD amongst 3 targeted dose levels of IV busulfan given with etoposide as prep therapy in pts with AML undergoing autologous stem cell transplantation. Safety is the primary goal. [ Time Frame: 3 yrs ] [ Designated as safety issue: Yes ]
- To achieve targeted busulfan levels following dose-adjustment of approximately (+/-) 10% in >80% of patients (i.e. target=1250 uMol*min, acceptable range 1125-1375 uMol*min, target=1400 uMol*min, acceptable range 1260-1540 ng/ml, etc) [ Time Frame: 3 yrs ] [ Designated as safety issue: Yes ]
|Study Start Date:||November 2009|
|Estimated Study Completion Date:||December 2017|
|Estimated Primary Completion Date:||December 2016 (Final data collection date for primary outcome measure)|
Show Detailed Description
Please refer to this study by its ClinicalTrials.gov identifier: NCT01048827
|United States, California|
|University of California Med. Center|
|San Francisco, California, United States, 94143|
|Study Chair:||Thomas Martin, MD||University of California Med. Center, SF|