Targeted, Dose-Escalation Busulfan-Etoposide as Prep Regimen

NCT01048827 | Completed Phase 1 DMC

• 1 other identifier: 82516
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Myeloid Leukemia

Keywords

AML; autologous transplant

Outcome Measures

Primary Outcomes (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.

  3 yrs

Secondary Outcomes (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)

  3 yrs

Study Arms (1)

experimental

EXPERIMENTAL

dose-escalation Busulfan

Drug: Busulfan

Interventions

Busulfan DRUG

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)\^

experimental

Eligibility Criteria

• Age: 18 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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

Sponsors & Collaborators

• University of California, San Francisco: lead

Study Sites (1)

University of California Med. Center

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Busulfan

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Thomas Martin, MD

  University of California Med. Center, SF

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 12, 2010
• First Posted: January 14, 2010
• Study Start: November 1, 2009
• Primary Completion: December 31, 2013
• Study Completion: February 25, 2015
• Last Updated: August 11, 2017

Record last verified: 2017-08

Locations

US (1)