Back to resultsAMD3100 Plus Mitoxantrone, Etoposide and Cytarabine in Acute Myeloid Leukemia (AMD3100+MEC)
Primary Purpose
Leukemia, Myeloid, Acute
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
AMD3100
Mitoxantrone
Etoposide
Cytarabine
Sponsored by
About this trial
This is an interventional treatment trial for Leukemia, Myeloid, Acute focused on measuring Plerixafor, CXCR4, Chemosensitization
Eligibility Criteria
Inclusion Criteria:
Acute myeloid leukemia diagnosed by WHO criteria with one of the following:
- Primary refractory disease following >= 1 rounds of induction chemotherapy
- First relapse or higher
- Age between 18 and 70 years of age
- Adequate organ function defined as Creatinine <= 1.5 x institutional ULN; AST, ALT, total bilirubin <= 2 x ULN; Left ventricular ejection fraction of >= 40% by MUGA scan
- 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 > 20 x 103 /mm3
- Active CNS involvement with leukemia
- Previous treatment with MEC or other regimen containing both mitoxantrone and etoposide
- Pregnant or nursing
- Receiving any other investigational agent
- Colony stimulating factors filgrastim, pegfilgrastim or sargramostim within 2 weeks of study
- Less than 2 weeks from the completion of any previous cytotoxic chemotherapy
- Severe concurrent illness that would limit compliance with study requirements
Sites / Locations
- Washington University
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Phase I Dose Escalation
Phase II Dose Treatment
Arm Description
AMD3100 SQ on days 0-5 Mitoxantrone on days 1-5 Etoposide on days 1-5 Cytarabine on days 1-5 Dose Level 1 AMD3100 dose = 80 mcg/kg/d Dose Level 2 AMD3100 dose = 160 mcg/kg/d
AMD 3100 SQ on days 0-5 Mitoxantrone on days 1-5 Etoposide on days 1-5 Cytarabine on days 1-5 Dose Level 3 AMD3100 dose=240 mcg/kg/d (this was the Phase II dose)
Outcomes
Primary Outcome Measures
Phase I Only: Optimal Dose of AMD3100 Plus MEC in Patients With Relapsed or Refractory AML
A standard 3+3 design was used in the Phase I portion starting with the AMD3100 dose of 80 mcg/kg and escalating by 80 mcg/kg for each successive cohort up to a maximum of 240 mcg/kg/d. The optimal dose was defined as the highest dose of AMD3100 <= 240 mcg/kg at which 0-1 of 6 patients experienced a dose limiting toxicity.
Phase II Only: Complete Response Rate of AMD3100 + MEC
Responses were assessed according to the International Working Group Criteria for AML. All patients who received at least one dose of AMD3100 were considered evaluable for response.
Response rate was the rate of complete remission plus complete remission with incomplete blood count recovery (CR + CRi).
Ability of AMD3100 + MEC to Induce dsDNA Damage and Apoptosis in Leukemic Blasts From Bone Marrow or Peripheral Blood Fractions
Secondary Outcome Measures
Safety and Tolerability of AMD3100 + MEC.
Treatment related mortality (deaths occurring during treatment)
Time to Neutrophil Recovery
Defined as the date of the first dose of AMD3100 to the date that the absolute neutrophil count >1,000 cells/mm^3.
Time to Platelet Recovery
Defined as the date of the first dose of AMD3100 to the date that the platelet count is >100,000/mm3 in the absence of platelet transfusions.
Characterize the Mobilization of Leukemic Cells With AMD3100 by Measuring the Peak Mobilization of Total Leukocytes (Phase I)
Measured at 0 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after AMD3100 dose on Day 0.
Characterization of the mobilized cells as well as the kinetics of mobilization will be determined by analyzing the surface expression of mobilized cells by flow cytometry at the specified time points in conjunction with their total leukocyte count from the patient's CBC.
Characterize the Mobilization of Leukemic Cells With AMD3100 by Measuring the Peak Mobilization of AML Blasts (Phase I)
Measured at 0 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after AMD3100 dose on Day 0.
Pharmacokinetics of AMD3100 on MEC
Time to Progression
Treatment Failure
Treatment failures includes those patients for whom treatment has failed to achieve a CR or a CRi.
Overall Survival
Relapse-free Survival
This is determined only for patients achieving a complete remission. Defined as the interval from the date of the first documentation of a leukemia free state to date of recurrence or death due to any cause.
Kaplain-Meier estimate was used.
Full Information
NCT ID
NCT00512252
First Posted
August 6, 2007
Last Updated
October 27, 2016
Sponsor
Washington University School of Medicine
1. Study Identification
Unique Protocol Identification Number
NCT00512252
Brief Title
AMD3100 Plus Mitoxantrone, Etoposide and Cytarabine in Acute Myeloid Leukemia
Acronym
AMD3100+MEC
Official Title
A Phase I/II Study of AMD3100 With Mitoxantrone, Etoposide and Cytarabine (AMD3100+MEC) in Relapsed or Refractory AML
Study Type
Interventional
2. Study Status
Record Verification Date
October 2016
Overall Recruitment Status
Completed
Study Start Date
July 2007 (undefined)
Primary Completion Date
June 2010 (Actual)
Study Completion Date
June 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
This study is a phase I/II study to determine the safety and efficacy of AMD3100 when combined with mitoxantrone, etoposide, and cytarabine in patients with relapsed or refractory AML.
We hypothesize that disrupting the interaction between AML blasts and the marrow microenvironment with AMD3100 may enhance the cytotoxic effect of chemotherapy.
Detailed Description
The interaction of leukemic blasts with the bone marrow microenvironment is postulated to be an important mediator of chemoresistance in AML. Although a number of receptor / ligand pairs have been implicated, the CXCR4 / SDF-1 axis functions as the principal regulator of homing and retention of both normal and malignant hematopoietic cells in the marrow. AMD3100 is a bicyclam molecule which reversibly blocks CXCR4 binding to SDF-1 and is being developed clinically as a mobilization agent for hematopoietic stem cell transplantation. Preclinical data from our group has demonstrated that in murine models, plerixafor can disrupt the interaction of leukemic cells with the marrow microenvironment and sensitize blasts to the effect of chemotherapy. Based on these data, we have initiated a phase I/II study in patients with relapsed or refractory AML in which plerixafor is administered prior to salvage chemotherapy.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myeloid, Acute
Keywords
Plerixafor, CXCR4, Chemosensitization
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
52 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Phase I Dose Escalation
Arm Type
Experimental
Arm Description
AMD3100 SQ on days 0-5
Mitoxantrone on days 1-5
Etoposide on days 1-5
Cytarabine on days 1-5
Dose Level 1 AMD3100 dose = 80 mcg/kg/d
Dose Level 2 AMD3100 dose = 160 mcg/kg/d
Arm Title
Phase II Dose Treatment
Arm Type
Experimental
Arm Description
AMD 3100 SQ on days 0-5
Mitoxantrone on days 1-5
Etoposide on days 1-5
Cytarabine on days 1-5
Dose Level 3 AMD3100 dose=240 mcg/kg/d (this was the Phase II dose)
Intervention Type
Drug
Intervention Name(s)
AMD3100
Other Intervention Name(s)
Plerixafor
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-U, Tarabine PFS
Primary Outcome Measure Information:
Title
Phase I Only: Optimal Dose of AMD3100 Plus MEC in Patients With Relapsed or Refractory AML
Description
A standard 3+3 design was used in the Phase I portion starting with the AMD3100 dose of 80 mcg/kg and escalating by 80 mcg/kg for each successive cohort up to a maximum of 240 mcg/kg/d. The optimal dose was defined as the highest dose of AMD3100 <= 240 mcg/kg at which 0-1 of 6 patients experienced a dose limiting toxicity.
Time Frame
Completion of all patients in Phase I portion (232 days)
Title
Phase II Only: Complete Response Rate of AMD3100 + MEC
Description
Responses were assessed according to the International Working Group Criteria for AML. All patients who received at least one dose of AMD3100 were considered evaluable for response.
Response rate was the rate of complete remission plus complete remission with incomplete blood count recovery (CR + CRi).
Time Frame
42 days
Title
Ability of AMD3100 + MEC to Induce dsDNA Damage and Apoptosis in Leukemic Blasts From Bone Marrow or Peripheral Blood Fractions
Time Frame
42 days
Secondary Outcome Measure Information:
Title
Safety and Tolerability of AMD3100 + MEC.
Description
Treatment related mortality (deaths occurring during treatment)
Time Frame
42 days
Title
Time to Neutrophil Recovery
Description
Defined as the date of the first dose of AMD3100 to the date that the absolute neutrophil count >1,000 cells/mm^3.
Time Frame
42 days
Title
Time to Platelet Recovery
Description
Defined as the date of the first dose of AMD3100 to the date that the platelet count is >100,000/mm3 in the absence of platelet transfusions.
Time Frame
42 days
Title
Characterize the Mobilization of Leukemic Cells With AMD3100 by Measuring the Peak Mobilization of Total Leukocytes (Phase I)
Description
Measured at 0 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after AMD3100 dose on Day 0.
Characterization of the mobilized cells as well as the kinetics of mobilization will be determined by analyzing the surface expression of mobilized cells by flow cytometry at the specified time points in conjunction with their total leukocyte count from the patient's CBC.
Time Frame
Day 0
Title
Characterize the Mobilization of Leukemic Cells With AMD3100 by Measuring the Peak Mobilization of AML Blasts (Phase I)
Description
Measured at 0 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after AMD3100 dose on Day 0.
Time Frame
Day 0
Title
Pharmacokinetics of AMD3100 on MEC
Time Frame
Day 1 - Phase 2 only
Title
Time to Progression
Time Frame
Every 6 months
Title
Treatment Failure
Description
Treatment failures includes those patients for whom treatment has failed to achieve a CR or a CRi.
Time Frame
42 days
Title
Overall Survival
Time Frame
1 year
Title
Relapse-free Survival
Description
This is determined only for patients achieving a complete remission. Defined as the interval from the date of the first documentation of a leukemia free state to date of recurrence or death due to any cause.
Kaplain-Meier estimate was used.
Time Frame
1 year
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 >= 1 rounds of induction chemotherapy
First relapse or higher
Age between 18 and 70 years of age
Adequate organ function defined as Creatinine <= 1.5 x institutional ULN; AST, ALT, total bilirubin <= 2 x ULN; Left ventricular ejection fraction of >= 40% by MUGA scan
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 > 20 x 103 /mm3
Active CNS involvement with leukemia
Previous treatment with MEC or other regimen containing both mitoxantrone and etoposide
Pregnant or nursing
Receiving any other investigational agent
Colony stimulating factors filgrastim, pegfilgrastim or sargramostim within 2 weeks of study
Less than 2 weeks from the completion of any previous cytotoxic chemotherapy
Severe concurrent illness that would limit compliance with study requirements
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Geoffrey L. Uy, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
22308295
Citation
Uy GL, Rettig MP, Motabi IH, McFarland K, Trinkaus KM, Hladnik LM, Kulkarni S, Abboud CN, Cashen AF, Stockerl-Goldstein KE, Vij R, Westervelt P, DiPersio JF. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood. 2012 Apr 26;119(17):3917-24. doi: 10.1182/blood-2011-10-383406. Epub 2012 Feb 2.
Results Reference
derived
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
AMD3100 Plus Mitoxantrone, Etoposide and Cytarabine in Acute Myeloid Leukemia
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