AMD3100 Plus Mitoxantrone, Etoposide and Cytarabine in Acute Myeloid Leukemia (AMD3100+MEC)

The Washington University

Status and phase: Completed; Phase 2; Phase 1

Conditions: Leukemia, Myeloid, Acute

Treatments: Drug: Mitoxantrone; Drug: Etoposide; Drug: Cytarabine; Drug: AMD3100

Study type: Interventional

Funder types: Other

Identifiers

NCT00512252

07-0227 / 201011796

Details and patient eligibility

About

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.

Full 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.

Enrollment: 52 patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. 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

2. Age between 18 and 70 years of age

3. 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

4. Women of childbearing potential and sexually active males must be willing and able to use effective contraception while on study

5. Able to provide signed informed consent prior to registration on study

Exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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52 participants in 2 patient groups

Phase I Dose Escalation

Experimental group

Description:

* 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

Treatment:

Drug: AMD3100

Drug: Cytarabine

Drug: Etoposide

Drug: Mitoxantrone

Phase II Dose Treatment

Experimental group

Description:

* 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)

Treatment:

Drug: AMD3100

Drug: Cytarabine

Drug: Etoposide

Drug: Mitoxantrone