AMD3100 Plus Mitoxantrone, Etoposide and Cytarabine in Acute Myeloid Leukemia (AMD3100+MEC)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT00512252
First received: August 6, 2007
Last updated: September 12, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Leukemia, Myeloid, Acute
Drug: AMD3100
Drug: Mitoxantrone
Drug: Etoposide
Drug: Cytarabine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of AMD3100 With Mitoxantrone, Etoposide and Cytarabine (AMD3100+MEC) in Relapsed or Refractory AML

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Phase I Only: Optimal Dose of AMD3100 Plus MEC in Patients With Relapsed or Refractory AML [ Time Frame: Completion of all patients in Phase I portion (232 days) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: 42 days ] [ Designated as safety issue: No ]

    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 [ Time Frame: 42 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Safety and Tolerability of AMD3100 + MEC. [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
    Treatment related mortality (deaths occurring during treatment)

  • Time to Neutrophil Recovery [ Time Frame: 42 days ] [ Designated as safety issue: No ]
    Defined as the date of the first dose of AMD3100 to the date that the absolute neutrophil count >1,000mm^3.

  • Time to Platelet Recovery [ Time Frame: 42 days ] [ Designated as safety issue: No ]
    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) [ Time Frame: Day 0 ] [ Designated as safety issue: No ]

    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) [ Time Frame: Day 0 ] [ Designated as safety issue: No ]
    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 Frame: Day 1 - Phase 2 only ] [ Designated as safety issue: No ]
  • Time to Progression [ Time Frame: Every 6 months ] [ Designated as safety issue: No ]
  • Treatment Failure [ Time Frame: 42 days ] [ Designated as safety issue: No ]
    Treatment failures includes those patients for whom treatment has failed to achieve a CR or a CRi.

  • Overall Survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  • Relapse-free Survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]

    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.



Enrollment: 52
Study Start Date: July 2007
Study Completion Date: June 2010
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase I Dose Escalation
  • 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

Drug: AMD3100
Other Name: Plerixafor
Drug: Mitoxantrone
Other Name: Novantrone
Drug: Etoposide
Other Names:
  • VP-16
  • Vepesid
  • Etopophos
Drug: Cytarabine
Other Names:
  • Ara-C
  • Cytosar-U
  • Tarabine PFS
Experimental: Phase II Dose Treatment
  • 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)

Drug: AMD3100
Other Name: Plerixafor
Drug: Mitoxantrone
Other Name: Novantrone
Drug: Etoposide
Other Names:
  • VP-16
  • Vepesid
  • Etopophos
Drug: Cytarabine
Other Names:
  • Ara-C
  • Cytosar-U
  • Tarabine PFS

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

    1. Primary refractory disease following >= 1 rounds of induction chemotherapy
    2. First relapse or higher
  2. Age between 18 and 70 years of age
  3. 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
  4. Women of childbearing potential and sexually active males must be willing and able to use effective contraception while on study
  5. 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. Receiving any other investigational agent
  7. Colony stimulating factors filgrastim, pegfilgrastim or sargramostim within 2 weeks of study
  8. Less than 2 weeks from the completion of any previous cytotoxic chemotherapy
  9. Severe concurrent illness that would limit compliance with study requirements
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00512252

Locations
United States, Missouri
Washington University
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Geoffrey L. Uy, MD Washington University Early Recognition Center
  More Information

Additional Information:
No publications provided by Washington University School of Medicine

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00512252     History of Changes
Other Study ID Numbers: 07-0227 / 201011796
Study First Received: August 6, 2007
Results First Received: July 28, 2014
Last Updated: September 12, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Washington University School of Medicine:
Plerixafor
CXCR4
Chemosensitization

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Etoposide
Mitoxantrone
Etoposide phosphate
Cytarabine
JM 3100
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Anti-HIV Agents

ClinicalTrials.gov processed this record on October 01, 2014