Targeted, Dose-Escalation Busulfan-Etoposide as Prep Regimen (Busulfan)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01048827
Recruitment Status : Completed
First Posted : January 14, 2010
Last Update Posted : August 11, 2017
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Busulfan Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (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
Study Start Date : November 2009
Actual Primary Completion Date : December 31, 2013
Actual Study Completion Date : February 25, 2015

Arm Intervention/treatment
Experimental: experimental
dose-escalation Busulfan
Drug: Busulfan
  1. 1250 uMol*min (AUC to time 6 hrs)^
  2. 1400 uMol*min (AUC to time 6 hrs
  3. 1550 uMol*min (AUC to time 6 hrs)^

Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. 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 ]

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Ages Eligible for Study:   18 Years to 69 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01048827

United States, California
University of California Med. Center
San Francisco, California, United States, 94143
Sponsors and Collaborators
University of California, San Francisco
Study Chair: Thomas Martin, MD University of California Med. Center, SF

Responsible Party: University of California, San Francisco Identifier: NCT01048827     History of Changes
Obsolete Identifiers: NCT00824525
Other Study ID Numbers: 82516
First Posted: January 14, 2010    Key Record Dates
Last Update Posted: August 11, 2017
Last Verified: August 2017

Keywords provided by University of California, San Francisco:
autologous transplant

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Alkylating Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Myeloablative Agonists