Chemosensitization With Plerixafor Plus G-CSF in Acute Myeloid Leukemia

• Phase I: To determine the maximum tolerated dose of plerixafor plus G-CSF when combined with MEC in patients with relapsed or refractory AML [ Time Frame: 45 days after start of treatment ] [ Designated as safety issue: Yes ]
• Phase II: To determine the complete response rate (CR+CRi) for plerixafor plus G-CSF when combined with MEC in patients with relapsed or refractory AML. [ Time Frame: 45 days ] [ Designated as safety issue: No ]

• To determine the safety and tolerability. [ Time Frame: 30 days following end of treatment ] [ Designated as safety issue: Yes ]
• To determine the time to hematologic recovery [ Time Frame: 45 days after start of therapy ] [ Designated as safety issue: No ]
• To characterize the mobilization of leukemic cells with plerixafor plus G-CSF. [ Time Frame: 8 days ] [ Designated as safety issue: No ]
• To characterize the effects of plerixafor plus G-CSF on SDF-1/CXCR4 signaling on leukemic blasts. [ Time Frame: 8 days ] [ Designated as safety issue: No ]
• To determine time to progression [ Time Frame: Every 6 months for up to 2 years ] [ Designated as safety issue: No ]
• Determine time to treatment failure [ Time Frame: 8 days ] [ Designated as safety issue: No ]
• Determine overall survival [ Time Frame: Every 6 months for 2 years ] [ Designated as safety issue: No ]

• Response rate (CR+CRi) [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
• Time to hematologic recovery [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
• Overall survival [ Time Frame: Duration of study ] [ Designated as safety issue: No ]
• Time to treatment failure [ Time Frame: Duration of study ] [ Designated as safety issue: No ]
• Rates of adverse events [ Time Frame: Duration of study ] [ Designated as safety issue: Yes ]

This study is designed to test the combination of Plerixafor with G-CSF for chemosensitization in patients with relapsed or refractory AML.

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 this study, we seek to maximize blockage of the SDF-1/CXCR4 axis through the following:

1. Addition of G-CSF, which down regulates SDF-1 expression and acts synergistically with plerixafor in stem cell mobilization
2. Intravenous instead of subcutaneous dosing of plerixafor to improve kinetics of administration.
3. Dose escalation of plerixafor and twice daily dosing to maintain maximum CXCR4 blockade.

• Drug: G-CSF
  Other Names:

  • filgrastim
  • Neupogen
• Drug: Plerixafor
  Other Names:

  • AMD3100
  • Mozobil
• Drug: Mitoxantrone
  Other Name: Novantrone
• Drug: Etoposide
  Other Names:

  • VP-16
  • Vepesid
  • Etopophos
• Drug: Cytarabine
  Other Names:

  • Ara-C
  • Cytosar

• Experimental: Dose Level 1
  • G-CSF 10 mcg/kg SQ on Days 1-8
  • Plerixafor 240 mcg/kg/d IV qd
  • Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
  • Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
  • Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
  Interventions:

  • Drug: G-CSF
  • Drug: Plerixafor
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine
• Experimental: Dose Level 2
  • G-CSF 10 mcg/kg SQ on Days 1-8
  • Plerixafor 320 mcg/kg/d IV qd
  • Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
  • Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
  • Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
  Interventions:

  • Drug: G-CSF
  • Drug: Plerixafor
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine
• Experimental: Dose Level 3
  • G-CSF 10 mcg/kg SQ on Days 1-8
  • Plerixafor 420 mcg/kg/d IV qd
  • Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
  • Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
  • Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
  Interventions:

  • Drug: G-CSF
  • Drug: Plerixafor
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine
• Experimental: Dose Level 4
  • G-CSF 10 mcg/kg SQ on Days 1-8
  • Plerixafor 560 mcg/kg/d IV qd
  • Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
  • Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
  • Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
  Interventions:

  • Drug: G-CSF
  • Drug: Plerixafor
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine
• Experimental: Dose Level 5
  • G-CSF 10 mcg/kg SQ on Days 1-8
  • Plerixafor 750 mcg/kg/d IV qd
  • Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
  • Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
  • Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
  Interventions:

  • Drug: G-CSF
  • Drug: Plerixafor
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine
• Experimental: MTD - Phase II
  • G-CSF MTD determined in Phase 1 SQ on Days 1-8
  • Plerixafor MTD determined in Phase 1 mcg/kg/d IV qd
  • Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
  • Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
  • Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
  Interventions:

  • Drug: G-CSF
  • Drug: Plerixafor
  • Drug: Mitoxantrone
  • Drug: Etoposide
  • Drug: Cytarabine

Inclusion Criteria:

1. Acute myeloid leukemia diagnosed by WHO criteria with one of the following:

   • Primary refractory disease following ≥ 1 round of induction chemotherapy
   • First relapse or higher
2. Age between 18 and 70 years old
3. ECOG performance status ≤ 3
4. Adequate organ function defined as:

Calculated creatinine clearance ≥ 50 ml/min AST, ALT, total bilirubin ≤ 2 x ULN except when in the opinion of treating physician is due to direct involvement of leukemia (eg. hepatic infiltration or biliary obstruction due to leukemia); Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram 5. Are surgically or biologically sterile or willing to practice acceptable birth control, as follows: i. Females of child bearing potential must agree to abstain from sexual activity or to use a medically approved contraceptive measure/regimen during and for 3 months after the treatment period. Women of child bearing potential must have a negative serum or urine pregnancy test at the time of enrollment. Acceptable methods of birth control include oral contraceptive, intrauterine device (IUD), transdermal/implanted or injected contraceptives and abstinence.

ii. Males must agree to abstain from sexual activity or agree to utilize a medically approved contraception method during and for 3 months after the treatment period 6. 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. Received any other investigational agent or cytotoxic chemotherapy (excluding hydroxyurea) within the preceding 2 weeks
7. Received colony stimulating factors filgrastim or sargramostim within 1 week or pegfilgrastim within 2 weeks of study
8. Severe concurrent illness that would limit compliance with study requirements