Clinical trial NCT00512252: AMD3100 Plus Mitoxantrone, Etoposide and Cytarabine in Acute Myeloid Leukemia
Official title: A Phase I/II Study of AMD3100 With Mitoxantrone, Etoposide and Cytarabine (AMD3100+MEC) in Relapsed or Refractory AML
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia, Myeloid, Acute
Keywords: Plerixafor
CXCR4
Chemosensitization
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2007-08-07
Enrollment: 52
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 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.

Eligibility 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

Primary outcomes:
measure: Phase I Only: Optimal Dose of AMD3100 Plus MEC in Patients With Relapsed or Refractory AML
timeFrame: Completion of all patients in Phase I portion (232 days)
measure: Phase II Only: Complete Response Rate of AMD3100 + MEC
timeFrame: 42 days
measure: Ability of AMD3100 + MEC to Induce dsDNA Damage and Apoptosis in Leukemic Blasts From Bone Marrow or Peripheral Blood Fractions
timeFrame: 42 days
Secondary outcomes:
measure: Safety and Tolerability of AMD3100 + MEC.
timeFrame: 42 days
measure: Time to Neutrophil Recovery
timeFrame: 42 days
measure: Time to Platelet Recovery
timeFrame: 42 days
measure: Characterize the Mobilization of Leukemic Cells With AMD3100 by Measuring the Peak Mobilization of Total Leukocytes (Phase I)
timeFrame: Day 0
measure: Characterize the Mobilization of Leukemic Cells With AMD3100 by Measuring the Peak Mobilization of AML Blasts (Phase I)
timeFrame: Day 0
measure: Pharmacokinetics of AMD3100 on MEC
timeFrame: Day 1 - Phase 2 only
measure: Time to Progression
timeFrame: Every 6 months
measure: Treatment Failure
timeFrame: 42 days
measure: Overall Survival
timeFrame: 1 year
measure: Relapse-free Survival
timeFrame: 1 year
Other outcomes:
Locations:
city: St. Louis
country: United States
facility: Washington University
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Geoffrey L. Uy, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.