Targeted, Dose-Escalation Busulfan-Etoposide as Prep Regimen

Completed · Phase 1

Conditions studied: Acute Myeloid Leukemia

In brief

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.

Key facts

Study ID

NCT01048827

Run by

University of California, San Francisco

People needed

12

Starts

2009-11-01

Expected to finish

2015-02-25

Last updated by the study team

2017-08-11

Who can join

Age: 18 and older, up to 69. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Before Consolidation Chemotherapy
• Age 18-69 years
• Diagnosis of AML
• CR with ≤2 courses of induction chemotherapy.
• Out of the hospital for a minimum of 4 weeks from induction chemotherapy or 3 weeks if consolidation chemotherapy has been administered.
• Remission bone marrow bx w/i 2 wks of beginning post remission rx.
• One cycle of post-remission consolidation w/standard dose cytarabine or HDAC with <8 doses of HDAC.
• Benign CSF: Lumbar puncture with cell count, differential and protein to determine lack of extramedullary leukemia required w/i 2 weeks of post- remission therapy IF CSF status is unknown or has been positive at dx.
• No active infection
• No evidence of prior liver disease.
• Creatinine <2.0 mg/dl.
• Cardiac ejection fraction ≥40%.
• Adequate pulmonary function with DLCO ≥40% of predicted.
• No co-morbid medical condition that would jeopardize the chance of tolerating aggressive chemotherapy.
• ECOG 0-2
• Signed informed consent.
• Eligibility to be Re-assessed Before Autologous SCT
• Minimum of 4 weeks out of hospital after post-remission rx.
• Continued CR documented by bone marrow morphology and cytogenetics (if previously abnormal), performed within 2 wks of admission for autologous transplantation.
• Adequate marrow recovery from post-remission therapy as demonstrated by an ANC ≥ 500/µl, platelets ≥ 50,000/µl and stable or improving hemoglobin (transfusion independent).
• Adequate peripheral stem cells collected and stored;
• No evidence of liver dysfunction as determined within 2 weeks of transplant admission. Bilirubin must be < 2.0 mg/dl and the AST and alkaline phosphatase < 3x the upper limit of normal.
• Creatinine < 2.0 mg/dl.
• No active infection or need for ongoing antibiotics.

Where it is running

• University of California Med. Center — San Francisco, California, United States

Full record on ClinicalTrials.gov

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