Targeted, Dose-Escalation Busulfan-Etoposide as Prep Regimen

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by University of California, San Francisco
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT01048827
First received: January 12, 2010
Last updated: August 13, 2013
Last verified: August 2013
  Purpose

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 Intervention Phase
Acute Myeloid Leukemia
Drug: Busulfan
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
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

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 48
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)
Arms Assigned Interventions
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)^

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 69 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01048827

Contacts
Contact: Thomas Martin, MD 415-353-9365 martint@medicine.ucsf.edu
Contact: Adrienne Moran 415-476-1402 morana@medicine.ucsf.edu

Locations
United States, California
University of California Med. Center Recruiting
San Francisco, California, United States, 94143
Contact: Thomas Martin, MD    415-353-9365    martint@medicine.ucsf.edu   
Sub-Investigator: Lloyd Damon, MD         
Sub-Investigator: Lawrence Kaplan, MD         
Sub-Investigator: Jeffrey Wolf, MD         
Sub-Investigator: Charalambos Andreadis, MD         
Sub-Investigator: Weiyun Ai, MD         
Sub-Investigator: Rebecca Olin, MD         
Sub-Investigator: Catherine Smith, MD         
Sub-Investigator: Karin Gaensler, MD         
Sponsors and Collaborators
University of California, San Francisco
Investigators
Study Chair: Thomas Martin, MD University of California Med. Center, SF
  More Information

No publications provided

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01048827     History of Changes
Obsolete Identifiers: NCT00824525
Other Study ID Numbers: 82516
Study First Received: January 12, 2010
Last Updated: August 13, 2013
Health Authority: United States: Institutional Review Board

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

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Busulfan
Etoposide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Myeloablative Agonists
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on July 26, 2014