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Chemosensitization With Plerixafor Plus G-CSF in Acute Myeloid Leukemia

Primary Purpose

Leukemia, Myeloid, Acute

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
G-CSF
Plerixafor
Mitoxantrone
Etoposide
Cytarabine
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Myeloid, Acute focused on measuring stem cell mobilization, chemosensitization, CXCR4, SDF-1, CXCL-12

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Dana Farber Cancer Institute
  • Washington University
  • MD Anderson Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Dose Level 1

Dose Level 2

Dose Level 3

Dose Level 4

Dose Level 5

MTD - Phase II

Arm 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

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

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

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

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

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

Outcomes

Primary Outcome Measures

Phase I: Maximum Tolerated Dose of Plerixafor Plus G-CSF When Combined With MEC
Phase II: Complete Response Rate (CR+CRi)
Morphologic complete remission (CR): Defined as morphologic leukemia-free state, including <5% blasts in BM aspirate with marrow spicules and a count of > 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC > 1,000/mm3, platelet count > 100,000/mm3. Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia <1,000/mm3 or thrombocytopenia <100,000/mm3.

Secondary Outcome Measures

Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency
Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery
-Neutrophil recovery is defined as absolute neutrophil count (ANC) >= 500/mm^3
Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery
-Neutrophil recovery is defined as absolute neutrophil count >= 1000/mm^3
Time to Hematologic Recovery as Measured by Time to Platelet Recovery
-Platelet recovery is defined as platelets >= 50,000/mm^3
Time to Hematologic Recovery as Measured by Time to Platelet Recovery
-Platelet recovery is defined as platelets >= 100,000/mm3
Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in White Blood Cells
Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in AML Blast Count
Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 1D9 Relative Mean Fluorescent Intensity
Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 12G5 Relative Mean Fluorescent Intensity
Time to Progression
Recurrence / morphologic relapse: Defined as reappearance of blasts in the blood or the finding of > 5% blasts in the BM, not attributable to any other cause. New dysplastic changes are considered a relapse. If there are no blasts in the peripheral blood and 5-19% blasts in the BM, the BM biopsy and aspirate should be repeated in > 1 week to confirm relapse.
Time to Treatment Failure
Overall Survival
Overall survival: Defined as the date of first dose of study drug to the date of death from any cause.

Full Information

First Posted
May 13, 2009
Last Updated
February 14, 2017
Sponsor
Washington University School of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT00906945
Brief Title
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

2. Study Status

Record Verification Date
February 2017
Overall Recruitment Status
Completed
Study Start Date
February 2011 (undefined)
Primary Completion Date
November 2012 (Actual)
Study Completion Date
September 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myeloid, Acute
Keywords
stem cell mobilization, chemosensitization, CXCR4, SDF-1, CXCL-12

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
39 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dose Level 1
Arm Type
Experimental
Arm 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
Arm Title
Dose Level 2
Arm Type
Experimental
Arm 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
Arm Title
Dose Level 3
Arm Type
Experimental
Arm 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
Arm Title
Dose Level 4
Arm Type
Experimental
Arm 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
Arm Title
Dose Level 5
Arm Type
Experimental
Arm 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
Arm Title
MTD - Phase II
Arm Type
Experimental
Arm 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
Intervention Type
Drug
Intervention Name(s)
G-CSF
Other Intervention Name(s)
filgrastim, Neupogen
Intervention Type
Drug
Intervention Name(s)
Plerixafor
Other Intervention Name(s)
AMD3100, Mozobil
Intervention Type
Drug
Intervention Name(s)
Mitoxantrone
Other Intervention Name(s)
Novantrone
Intervention Type
Drug
Intervention Name(s)
Etoposide
Other Intervention Name(s)
VP-16, Vepesid, Etopophos
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Other Intervention Name(s)
Ara-C, Cytosar
Primary Outcome Measure Information:
Title
Phase I: Maximum Tolerated Dose of Plerixafor Plus G-CSF When Combined With MEC
Time Frame
Completion of Phase I enrollment (17 months)
Title
Phase II: Complete Response Rate (CR+CRi)
Description
Morphologic complete remission (CR): Defined as morphologic leukemia-free state, including <5% blasts in BM aspirate with marrow spicules and a count of > 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC > 1,000/mm3, platelet count > 100,000/mm3. Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia <1,000/mm3 or thrombocytopenia <100,000/mm3.
Time Frame
45 days
Secondary Outcome Measure Information:
Title
Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency
Time Frame
30 days following end of treatment
Title
Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery
Description
-Neutrophil recovery is defined as absolute neutrophil count (ANC) >= 500/mm^3
Time Frame
Up to 62 days after treatment
Title
Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery
Description
-Neutrophil recovery is defined as absolute neutrophil count >= 1000/mm^3
Time Frame
Up to 62 days after treatment
Title
Time to Hematologic Recovery as Measured by Time to Platelet Recovery
Description
-Platelet recovery is defined as platelets >= 50,000/mm^3
Time Frame
Up to 62 days after treatment
Title
Time to Hematologic Recovery as Measured by Time to Platelet Recovery
Description
-Platelet recovery is defined as platelets >= 100,000/mm3
Time Frame
Up to 62 days after treatment
Title
Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in White Blood Cells
Time Frame
6 hours after plerixafor
Title
Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in AML Blast Count
Time Frame
6 hours after plerixafor
Title
Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 1D9 Relative Mean Fluorescent Intensity
Time Frame
6 hours after plerixafor
Title
Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 12G5 Relative Mean Fluorescent Intensity
Time Frame
6 hours after plerixafor
Title
Time to Progression
Description
Recurrence / morphologic relapse: Defined as reappearance of blasts in the blood or the finding of > 5% blasts in the BM, not attributable to any other cause. New dysplastic changes are considered a relapse. If there are no blasts in the peripheral blood and 5-19% blasts in the BM, the BM biopsy and aspirate should be repeated in > 1 week to confirm relapse.
Time Frame
2 years
Title
Time to Treatment Failure
Time Frame
8 days
Title
Overall Survival
Description
Overall survival: Defined as the date of first dose of study drug to the date of death from any cause.
Time Frame
Median follow-up was 34.6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 Age between 18 and 70 years old ECOG performance status ≤ 3 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 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 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 ≥ 20 x 103 /mm3 Active CNS involvement with leukemia Previous treatment with MEC or other regimen containing both mitoxantrone and etoposide Pregnant or nursing Received any other investigational agent or cytotoxic chemotherapy (excluding hydroxyurea) within the preceding 2 weeks Received colony stimulating factors filgrastim or sargramostim within 1 week or pegfilgrastim within 2 weeks of study Severe concurrent illness that would limit compliance with study requirements
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Geoffrey L. Uy, M.D.
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Washington University
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.siteman.wustl.edu
Description
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Learn more about this trial

Chemosensitization With Plerixafor Plus G-CSF in Acute Myeloid Leukemia

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