Chemosensitization With Plerixafor Plus G-CSF in Acute Myeloid Leukemia

The Washington University

Status and phase: Completed; Phase 2; Phase 1

Conditions: Leukemia, Myeloid, Acute

Treatments: Drug: G-CSF; Drug: Cytarabine; Drug: Plerixafor; Drug: Etoposide; Drug: Mitoxantrone

Study type: Interventional

Funder types: Other

Identifiers

NCT00906945

10-0910 / 201106039

Details and patient eligibility

About

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

Full description

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.

Enrollment: 39 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:

   • Primary refractory disease following no more than 2 cycles of induction chemotherapy
   • First relapse with no prior unsuccessful salvage chemotherapy

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:

   • 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.
   • 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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39 participants in 6 patient groups

Dose Level 1

Experimental group

Description:

* 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

Treatment:

Drug: Mitoxantrone

Drug: Etoposide

Drug: Plerixafor

Drug: Cytarabine

Drug: G-CSF

Dose Level 2

Experimental group

Description:

* 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

Treatment:

Drug: Mitoxantrone

Drug: Etoposide

Drug: Plerixafor

Drug: Cytarabine

Drug: G-CSF

Dose Level 3

Experimental group

Description:

* 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

Treatment:

Drug: Mitoxantrone

Drug: Etoposide

Drug: Plerixafor

Drug: Cytarabine

Drug: G-CSF

Dose Level 4

Experimental group

Description:

* 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

Treatment:

Drug: Mitoxantrone

Drug: Etoposide

Drug: Plerixafor

Drug: Cytarabine

Drug: G-CSF

Dose Level 5

Experimental group

Description:

* 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

Treatment:

Drug: Mitoxantrone

Drug: Etoposide

Drug: Plerixafor

Drug: Cytarabine

Drug: G-CSF

MTD - Phase II

Experimental group

Description:

* 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

Treatment:

Drug: Mitoxantrone

Drug: Etoposide

Drug: Plerixafor

Drug: Cytarabine

Drug: G-CSF