AMD3100 Plus Mitoxantrone, Etoposide and Cytarabine in Acute Myeloid Leukemia

Phase 1

Completed

Conditions: Leukemia, Myeloid, Acute

Interventions: Drug: AMD3100
Drug: Mitoxantrone
Drug: Etoposide
Drug: Cytarabine

Registration Number: NCT00512252

Lead Sponsor: Washington University School of Medicine

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

Inclusion Criteria

Acute myeloid leukemia diagnosed by WHO criteria with one of the following:
1. Primary refractory disease following >= 1 rounds of induction chemotherapy
2. First relapse or higher
Age between 18 and 70 years of age
Adequate organ function defined as Creatinine <= 1.5 x institutional ULN; AST, ALT, total bilirubin <= 2 x ULN; Left ventricular ejection fraction of >= 40% by MUGA scan
Women of childbearing potential and sexually active males must be willing and able to use effective contraception while on study
Able to provide signed informed consent prior to registration on study

Exclusion Criteria

Acute promyelocytic leukemia (AML with t(15;17)(q22;q11) and variants)
Peripheral blood blast count > 20 x 103 /mm3
Active CNS involvement with leukemia
Previous treatment with MEC or other regimen containing both mitoxantrone and etoposide
Pregnant or nursing
Receiving any other investigational agent
Colony stimulating factors filgrastim, pegfilgrastim or sargramostim within 2 weeks of study
Less than 2 weeks from the completion of any previous cytotoxic chemotherapy
Severe concurrent illness that would limit compliance with study requirements

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase I Dose Escalation	Etoposide	* AMD3100 SQ on days 0-5 * Mitoxantrone on days 1-5 * Etoposide on days 1-5 * Cytarabine on days 1-5 Dose Level 1 AMD3100 dose = 80 mcg/kg/d Dose Level 2 AMD3100 dose = 160 mcg/kg/d
Phase II Dose Treatment	AMD3100	* AMD 3100 SQ on days 0-5 * Mitoxantrone on days 1-5 * Etoposide on days 1-5 * Cytarabine on days 1-5 Dose Level 3 AMD3100 dose=240 mcg/kg/d (this was the Phase II dose)
Phase I Dose Escalation	AMD3100	* AMD3100 SQ on days 0-5 * Mitoxantrone on days 1-5 * Etoposide on days 1-5 * Cytarabine on days 1-5 Dose Level 1 AMD3100 dose = 80 mcg/kg/d Dose Level 2 AMD3100 dose = 160 mcg/kg/d
Phase I Dose Escalation	Mitoxantrone	* AMD3100 SQ on days 0-5 * Mitoxantrone on days 1-5 * Etoposide on days 1-5 * Cytarabine on days 1-5 Dose Level 1 AMD3100 dose = 80 mcg/kg/d Dose Level 2 AMD3100 dose = 160 mcg/kg/d
Phase I Dose Escalation	Cytarabine	* AMD3100 SQ on days 0-5 * Mitoxantrone on days 1-5 * Etoposide on days 1-5 * Cytarabine on days 1-5 Dose Level 1 AMD3100 dose = 80 mcg/kg/d Dose Level 2 AMD3100 dose = 160 mcg/kg/d
Phase II Dose Treatment	Mitoxantrone	* AMD 3100 SQ on days 0-5 * Mitoxantrone on days 1-5 * Etoposide on days 1-5 * Cytarabine on days 1-5 Dose Level 3 AMD3100 dose=240 mcg/kg/d (this was the Phase II dose)
Phase II Dose Treatment	Etoposide	* AMD 3100 SQ on days 0-5 * Mitoxantrone on days 1-5 * Etoposide on days 1-5 * Cytarabine on days 1-5 Dose Level 3 AMD3100 dose=240 mcg/kg/d (this was the Phase II dose)
Phase II Dose Treatment	Cytarabine	* AMD 3100 SQ on days 0-5 * Mitoxantrone on days 1-5 * Etoposide on days 1-5 * Cytarabine on days 1-5 Dose Level 3 AMD3100 dose=240 mcg/kg/d (this was the Phase II dose)

Primary Outcome Measures

Name	Time	Method
Phase I Only: Optimal Dose of AMD3100 Plus MEC in Patients With Relapsed or Refractory AML	Completion of all patients in Phase I portion (232 days)	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.
Phase II Only: Complete Response Rate of AMD3100 + MEC	42 days	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).
Ability of AMD3100 + MEC to Induce dsDNA Damage and Apoptosis in Leukemic Blasts From Bone Marrow or Peripheral Blood Fractions	42 days

Secondary Outcome Measures

Name	Time	Method
Time to Progression	Every 6 months
Safety and Tolerability of AMD3100 + MEC.	42 days	Treatment related mortality (deaths occurring during treatment)
Time to Neutrophil Recovery	42 days	Defined as the date of the first dose of AMD3100 to the date that the absolute neutrophil count \>1,000 cells/mm\^3.
Time to Platelet Recovery	42 days	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.
Characterize the Mobilization of Leukemic Cells With AMD3100 by Measuring the Peak Mobilization of Total Leukocytes (Phase I)	Day 0	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.
Characterize the Mobilization of Leukemic Cells With AMD3100 by Measuring the Peak Mobilization of AML Blasts (Phase I)	Day 0	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.
Pharmacokinetics of AMD3100 on MEC	Day 1 - Phase 2 only
Treatment Failure	42 days	Treatment failures includes those patients for whom treatment has failed to achieve a CR or a CRi.
Overall Survival	1 year
Relapse-free Survival	1 year	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.