AMD3100 Plus Mitoxantrone, Etoposide and Cytarabine in Acute Myeloid Leukemia

Leukemia, Myeloid, Acute Clinical Trial

— AMD3100+MEC  

Official title:

A Phase I/II Study of AMD3100 With Mitoxantrone, Etoposide and Cytarabine (AMD3100+MEC) in Relapsed or Refractory AML

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00512252
• Other study ID #: 07-0227 / 201011796
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: August 6, 2007
• Last updated: September 12, 2014
• Start date: July 2007
• Est. completion date: June 2010

Study information

• Verified date: September 2014
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: June 2010
• Est. primary completion date: June 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• AMD3100

• Mitoxantrone

• Etoposide

• Cytarabine

Locations

Country	Name	City	State
United States	Washington University	St. Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Completion of all patients in Phase I portion (232 days)	Yes
Primary	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).	42 days	No
Primary	Ability of AMD3100 + MEC to Induce dsDNA Damage and Apoptosis in Leukemic Blasts From Bone Marrow or Peripheral Blood Fractions		42 days	No
Secondary	Safety and Tolerability of AMD3100 + MEC.	Treatment related mortality (deaths occurring during treatment)	42 days	Yes
Secondary	Time to Neutrophil Recovery	Defined as the date of the first dose of AMD3100 to the date that the absolute neutrophil count >1,000mm^3.	42 days	No
Secondary	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.	42 days	No
Secondary	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.	Day 0	No
Secondary	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.	Day 0	No
Secondary	Pharmacokinetics of AMD3100 on MEC		Day 1 - Phase 2 only	No
Secondary	Time to Progression		Every 6 months	No
Secondary	Treatment Failure	Treatment failures includes those patients for whom treatment has failed to achieve a CR or a CRi.	42 days	No
Secondary	Overall Survival		1 year	No
Secondary	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.	1 year	No

External Links

•   Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine