This study is a phase I/II study to determine the safety and efficacy of AMD3100 when combined with mitoxantrone, etoposide, and cytarabine in patients with relapsed or refractory AML. We hypothesize that disrupting the interaction between AML blasts and the marrow microenvironment with AMD3100 may enhance the cytotoxic effect of chemotherapy.
The interaction of leukemic blasts with the bone marrow microenvironment is postulated to be an important mediator of chemoresistance in AML. Although a number of receptor / ligand pairs have been implicated, the CXCR4 / SDF-1 axis functions as the principal regulator of homing and retention of both normal and malignant hematopoietic cells in the marrow. AMD3100 is a bicyclam molecule which reversibly blocks CXCR4 binding to SDF-1 and is being developed clinically as a mobilization agent for hematopoietic stem cell transplantation. Preclinical data from our group has demonstrated that in murine models, plerixafor can disrupt the interaction of leukemic cells with the marrow microenvironment and sensitize blasts to the effect of chemotherapy. Based on these data, we have initiated a phase I/II study in patients with relapsed or refractory AML in which plerixafor is administered prior to salvage chemotherapy.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
52
Washington University
St Louis, Missouri, United States
Phase I Only: Optimal Dose of AMD3100 Plus MEC in Patients With Relapsed or Refractory AML
A standard 3+3 design was used in the Phase I portion starting with the AMD3100 dose of 80 mcg/kg and escalating by 80 mcg/kg for each successive cohort up to a maximum of 240 mcg/kg/d. The optimal dose was defined as the highest dose of AMD3100 \<= 240 mcg/kg at which 0-1 of 6 patients experienced a dose limiting toxicity.
Time frame: Completion of all patients in Phase I portion (232 days)
Phase II Only: Complete Response Rate of AMD3100 + MEC
Responses were assessed according to the International Working Group Criteria for AML. All patients who received at least one dose of AMD3100 were considered evaluable for response. Response rate was the rate of complete remission plus complete remission with incomplete blood count recovery (CR + CRi).
Time frame: 42 days
Ability of AMD3100 + MEC to Induce dsDNA Damage and Apoptosis in Leukemic Blasts From Bone Marrow or Peripheral Blood Fractions
Time frame: 42 days
Safety and Tolerability of AMD3100 + MEC.
Treatment related mortality (deaths occurring during treatment)
Time frame: 42 days
Time to Neutrophil Recovery
Defined as the date of the first dose of AMD3100 to the date that the absolute neutrophil count \>1,000 cells/mm\^3.
Time frame: 42 days
Time to Platelet Recovery
Defined as the date of the first dose of AMD3100 to the date that the platelet count is \>100,000/mm3 in the absence of platelet transfusions.
Time frame: 42 days
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Characterize the Mobilization of Leukemic Cells With AMD3100 by Measuring the Peak Mobilization of Total Leukocytes (Phase I)
Measured at 0 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after AMD3100 dose on Day 0. Characterization of the mobilized cells as well as the kinetics of mobilization will be determined by analyzing the surface expression of mobilized cells by flow cytometry at the specified time points in conjunction with their total leukocyte count from the patient's CBC.
Time frame: Day 0
Characterize the Mobilization of Leukemic Cells With AMD3100 by Measuring the Peak Mobilization of AML Blasts (Phase I)
Measured at 0 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after AMD3100 dose on Day 0.
Time frame: Day 0
Pharmacokinetics of AMD3100 on MEC
Time frame: Day 1 - Phase 2 only
Time to Progression
Time frame: Every 6 months
Treatment Failure
Treatment failures includes those patients for whom treatment has failed to achieve a CR or a CRi.
Time frame: 42 days
Overall Survival
Time frame: 1 year
Relapse-free Survival
This is determined only for patients achieving a complete remission. Defined as the interval from the date of the first documentation of a leukemia free state to date of recurrence or death due to any cause. Kaplain-Meier estimate was used.
Time frame: 1 year