AMD3100 Plus Mitoxantrone, Etoposide and Cytarabine in Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: AMD3100
* Drug: Mitoxantrone
* Drug: Etoposide
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Dose Escalation<br>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<br> <br> * Other names: Plerixafor;Drug: Mitoxantrone<br> <br> * Other names: Novantrone;Drug: Etoposide<br> <br> * Other names: Etopophos;Drug: Cytarabine<br> <br> * Other names: Tarabine PFS;|
| Experimental: Phase II Dose Treatment<br>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<br> <br> * Other names: Plerixafor;Drug: Mitoxantrone<br> <br> * Other names: Novantrone;Drug: Etoposide<br> <br> * Other names: Etopophos;Drug: Cytarabine<br> <br> * Other names: Tarabine PFS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 | 
| Ability of AMD3100 + MEC to Induce dsDNA Damage and Apoptosis in Leukemic Blasts From Bone Marrow or Peripheral Blood Fractions |  | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of AMD3100 + MEC. | Treatment related mortality (deaths occurring during treatment) | 42 days | 
| 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. | 42 days | 
| 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 | 
| 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 | 
| 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 | 
| Pharmacokinetics of AMD3100 on MEC |  | Day 1 - Phase 2 only | 
| Time to Progression |  | Every 6 months | 
| Treatment Failure | Treatment failures includes those patients for whom treatment has failed to achieve a CR or a CRi. | 42 days | 
| Overall Survival |  | 1 year | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Plerixafor, CXCR4, Chemosensitization