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

• To determine the optimal dose and schedule of AMD3100 plus MEC in patients with relapsed or refractory AML [ Time Frame: Length of Phase I ] [ Designated as safety issue: Yes ]
• Determine the complete response rate of AMD3100 + MEC [ Time Frame: Phase II only ] [ Designated as safety issue: No ]
• Determine the ability of AMD3100 + MEC to induce dsDNA damage and apoptosis in leukemic blasts from bone marrow or peripheral blood fractions [ Time Frame: Length of study ] [ Designated as safety issue: No ]

• To determine the safety and tolerability of AMD3100 + MEC. [ Time Frame: Length of study ] [ Designated as safety issue: Yes ]
• To determine the time to hematologic recovery, time to progression, time to treatment failure, and overall survival of patients treated with AMD3100 + MEC. [ Time Frame: Length of study ] [ Designated as safety issue: No ]
• To characterize the mobilization of leukemic cells with AMD3100 [ Time Frame: 1 day ] [ Designated as safety issue: No ]
• Determine the pharmacokinetics of AMD3100 on MEC [ Time Frame: Day 1 ] [ Designated as safety issue: No ]

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.

• Drug: AMD3100
  • Dose Level 1: 80 mcg/kg/day SQ on days 0-5
  • Dose Level 2: 160 mcg/kg/day SQ on days 0-5
  • Dose Level 3: 240 mcg/kg/day SQ on days 0-5
  Other Name: Plerixafor
• Drug: Mitoxantrone
  8 mg/m2/day IV on days 1-5
  Other Name: Novantrone
• Drug: Etoposide
  100 mg/m2/day IV on days 1-5
  Other Names:

  • VP-16
  • Vepesid
  • Etopophos
• Drug: Cytarabine
  1000mg/m2/day IV on days 1-5
  Other Names:

  • Ara-C
  • Cytosar-U
  • Tarabine PFS

• Experimental: Dose Level 1
  AMD 3100 80 mcg/kg SQ, Mitoxantrone 8 mg/m2 x 5 days, Etoposide 100 mg/m2 x 5 days, Cytarabine 1000 mg/m2 x 5 days
  Interventions:

  • Drug: AMD3100
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine
• Experimental: Dose Level 2
  AMD 3100 160 mcg/kg SQ, Mitoxantrone 8 mg/m2 x 5 days, Etoposide 100 mg/m2 x 5 days, Cytarabine 1000 mg/m2 x 5 days
  Interventions:

  • Drug: AMD3100
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine
• Experimental: Dose Level 3
  AMD 3100 240 mcg/kg SQ, Mitoxantrone 8 mg/m2 x 5 days, Etoposide 100 mg/m2 x 5 days, Cytarabine 1000 mg/m2 x 5 days
  Interventions:

  • Drug: AMD3100
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine

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