IV Plerixafor With Mitoxantrone Etoposide and Cytarabine for Acute Myeloid Leukemia (AML)

• To determine the complete response rate (CR) for plerixafor when combined with MEC in patients with relapsed or refractory AML. [ Time Frame: Between days 15-42 ] [ Designated as safety issue: No ]
• To determine the safety and tolerability of plerixafor in combination with MEC [ Time Frame: Days 1-42 ] [ Designated as safety issue: Yes ]
• To determine the PK and explore potential PK drug-drug interactions between plerixafor and MEC. [ Time Frame: Predose, 15 min, 30 min , and 10 hrs ] [ Designated as safety issue: No ]
• To determine the time to hematologic recovery, overall survival, event-free survival, duration of remission, relapse-free survival, and overall survival. [ Time Frame: Until event ] [ Designated as safety issue: No ]
• To characterize the mobilization of leukemic cells with plerixafor plus G-CSF. [ Time Frame: Baseline, 6 hours ] [ Designated as safety issue: No ]
• To characterize the effects of plerixafor plus G-CSF on SDF-1/CXCR4 signaling on leukemic blasts. [ Time Frame: Baseline, 6 hours ] [ Designated as safety issue: No ]

• To determine the complete response rate (CR) for plerixafor when combined with MEC in patients with relapsed or refractory AML. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• To determine the safety and tolerability of plerixafor in combination with MEC [ Time Frame: 1 years ] [ Designated as safety issue: Yes ]
• To determine the PK and explore potential PK drug-drug interactions between plerixafor and MEC. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
• To determine the time to hematologic recovery, overall survival, event-free survival, duration of remission,relapse-free survival, and overall survival. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• To characterize the mobilization of leukemic cells with plerixafor plus G-CSF. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• To characterize the effects of plerixafor plus G-CSF on SDF-1/CXCR4 signaling on leukemic blasts. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

In this phase I extension study, the investigators seek to test the safety of both higher doses of plerixafor as well as intravenous dosing to maximize inhibition of the target, CXCR4.

In this study, we are seeking to target the leukemia microenvironment to overcome disease resistance. We hypothesize that by disrupting the interaction of leukemic blasts with the bone marrow microenvironment, we may sensitize leukemic blasts to the effects of cytotoxic chemotherapy. In current formulations, the volume of plerixafor required to administer doses higher than 240 mcg/kg may result in significant discomfort with repeated daily injections. In this phase I extension study, we seek to test the safety of both higher doses of plerixafor as well as intravenous dosing to maximize inhibition of the target, CXCR4.

• Drug: Plerixafor
  Plerixafor IV 240-560 mcg/kg/day IV on Days 0 thru Day 5
  Other Names:

  • AMD3100
  • Mozobil
• Drug: Mitoxantrone
  Mitoxantrone 8 mg/m2/day IV on Days 1 thru 5 starting 4-5 hours after plerixafor
  Other Name: Novantrone
• Drug: Etoposide
  Etoposide 100 mg/m2/day IV on over 60 minutes once daily on Days 1 thru 5
  Other Names:

  • Etopophos
  • Toposar
  • VePesid
  • VP156
• Drug: Cytarabine
  Cytarabine 1,000 mg/m2/day IV over 60 minutes once daily on days 1-5
  Other Names:

  • Cytosar-U
  • Ara-C
  • Cytosine arabinoside

• Experimental: Dose Level -1
  Mitoxantrone + Etoposide + Cytarabine + Plerixafor 240 mcg/kg/day IV
  Interventions:

  • Drug: Plerixafor
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine
• Experimental: Dose Level 1
  Mitoxantrone + Etoposide + Cytarabine + Plerixafor 320 mcg/kg/day IV
  Interventions:

  • Drug: Plerixafor
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine
• Experimental: Dose Level 2
  Mitoxantrone + Etoposide + Cytarabine + Plerixafor 420 mcg/kg/day IV
  Interventions:

  • Drug: Plerixafor
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine
• Experimental: Dose Level 3
  Mitoxantrone + Etoposide + Cytarabine + Plerixafor 560 mcg/kg/day IV
  Interventions:

  • Drug: Plerixafor
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine

Inclusion Criteria:

• Acute myeloid leukemia diagnosed according to WHO criteria with one of the following:

  • Primary refractory disease following ≥ 1 round of induction chemotherapy
  • First relapse or higher
• Age between 18 and 70 years
• ECOG performance status ≤ 2

• Adequate organ function defined as:

  • Creatinine ≤ 1.5 x institutional ULN
  • AST ≤ 2 x ULN except when in the opinion of treating physician is due to direct involvement of leukemia (e.g., hepatic infiltration or biliary obstruction due to leukemia)
  • ALT ≤ 2 x ULN except when in the opinion of treating physician is due to direct involvement of leukemia (e.g., hepatic infiltration or biliary obstruction due to leukemia)
  • Total bilirubin ≤ 2 x ULN except when in the opinion of treating physician is due to direct involvement of leukemia (e.g., hepatic infiltration or biliary obstruction due to leukemia)
  • Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram
• 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 ≥ 50 x 103 /mm3
• Active CNS involvement with leukemia
• Previous treatment with MEC or other regimen containing both mitoxantrone and etoposide
• Pregnant or nursing
• Concurrently receiving any other investigational agent
• Received colony stimulating factors filgrastim or sargramostim within 48 hours or pegfilgrastim within 14 days of study
• Less than 2 weeks from the completion of any previous cytotoxic chemotherapy (excluding hydroxyurea)
• Severe concurrent illness that would limit compliance with study requirements