Clinical trial NCT00906945: Chemosensitization With Plerixafor Plus G-CSF in Acute Myeloid Leukemia
Official title: Chemosensitization With Plerixafor Plus G-CSF in Relapsed or Refractory Acute Myeloid Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia, Myeloid, Acute
Keywords: stem cell mobilization
chemosensitization
CXCR4
SDF-1
CXCL-12
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2009-05-21
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Phase I: Maximum Tolerated Dose of Plerixafor Plus G-CSF When Combined With MEC
timeFrame: Completion of Phase I enrollment (17 months)
measure: Phase II: Complete Response Rate (CR+CRi)
timeFrame: 45 days
Secondary outcomes:
measure: Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency
timeFrame: 30 days following end of treatment
measure: Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery
timeFrame: Up to 62 days after treatment
measure: Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery
timeFrame: Up to 62 days after treatment
measure: Time to Hematologic Recovery as Measured by Time to Platelet Recovery
timeFrame: Up to 62 days after treatment
measure: Time to Hematologic Recovery as Measured by Time to Platelet Recovery
timeFrame: Up to 62 days after treatment
measure: Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in White Blood Cells
timeFrame: 6 hours after plerixafor
measure: Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in AML Blast Count
timeFrame: 6 hours after plerixafor
measure: Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 1D9 Relative Mean Fluorescent Intensity
timeFrame: 6 hours after plerixafor
measure: Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 12G5 Relative Mean Fluorescent Intensity
timeFrame: 6 hours after plerixafor
measure: Time to Progression
timeFrame: 2 years
measure: Time to Treatment Failure
timeFrame: 8 days
measure: Overall Survival
timeFrame: Median follow-up was 34.6 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: St. Louis
country: United States
facility: Washington University
state: Missouri
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Washington University School of Medicine
name: Geoffrey L. Uy, M.D.
role: PRINCIPAL_INVESTIGATOR
References: