IV Plerixafor With Mitoxantrone Etoposide and Cytarabine for Acute Myeloid Leukemia (AML)

Study Overview
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Brief Summary
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In this phase I extension study, the investigators seek to test the safety of both higher doses of plerixafor as well as intravenous dosing to maximize inhibition of the target, CXCR4.

Detailed Description
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In this study, we are seeking to target the leukemia microenvironment to overcome disease resistance. We hypothesize that by disrupting the interaction of leukemic blasts with the bone marrow microenvironment, we may sensitize leukemic blasts to the effects of cytotoxic chemotherapy. In current formulations, the volume of plerixafor required to administer doses higher than 240 mcg/kg may result in significant discomfort with repeated daily injections. In this phase I extension study, we seek to test the safety of both higher doses of plerixafor as well as intravenous dosing to maximize inhibition of the target, CXCR4.

Official Title
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A Phase I Study of Intravenous Plerixafor in Combination With Mitoxantrone Etoposide and Cytarabine for Relapsed or Refractory Acute Myeloid Leukemia

Conditions
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Leukemia, Myeloid, Acute

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute myeloid leukemia diagnosed according to WHO criteria with one of the following: Primary refractory disease following ≥ 1 round of induction chemotherapy First relapse or higher Age between 18 and 70 years ECOG performance status ≤ 2 Adequate organ function defined as: Creatinine ≤ 1.5 x institutional ULN AST ≤ 2 x ULN except when in the opinion of treating physician is due to direct involvement of leukemia (e.g., hepatic infiltration or biliary obstruction due to leukemia) ALT ≤ 2 x ULN except when in the opinion of treating physician is due to direct involvement of leukemia (e.g., hepatic infiltration or biliary obstruction due to leukemia) Total bilirubin ≤ 2 x ULN except when in the opinion of treating physician is due to direct involvement of leukemia (e.g., hepatic infiltration or biliary obstruction due to leukemia) Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram 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 ≥ 50 x 103 /mm3 Active CNS involvement with leukemia Previous treatment with MEC or other regimen containing both mitoxantrone and etoposide Pregnant or nursing Concurrently receiving any other investigational agent Received colony stimulating factors filgrastim or sargramostim within 48 hours or pegfilgrastim within 14 days of study Less than 2 weeks from the completion of any previous cytotoxic chemotherapy (excluding hydroxyurea) 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level 1<br>Mitoxantrone 8 mg/m2/day IV over 30 minutes once daily on days 1-5 Plerixafor 320 mcg/kg/day IV over 30 minutes on days 0-5 Etoposide 100 mg/m2/day IV over 60 minutes once daily on days 1-5 Cytarabine 1000 mg/m2/day IV over 60 minutes once daily on days 1-5 | Drug: Plerixafor<br> <br> * Other names: Mozobil;Drug: Mitoxantrone<br> <br> * Other names: Novantrone;Drug: Etoposide<br> <br> * Other names: VP156;Drug: Cytarabine<br> <br> * Other names: Cytosine arabinoside;|
| Experimental: Dose Level 2<br>Mitoxantrone 8 mg/m2/day IV over 30 minutes once daily on days 1-5 Plerixafor 420 mcg/kg/day IV over 30 minutes on days 0-5 Etoposide 100 mg/m2/day IV over 60 minutes once daily on days 1-5 Cytarabine 1000 mg/m2/day IV over 60 minutes once daily on days 1-5 | Drug: Plerixafor<br> <br> * Other names: Mozobil;Drug: Mitoxantrone<br> <br> * Other names: Novantrone;Drug: Etoposide<br> <br> * Other names: VP156;Drug: Cytarabine<br> <br> * Other names: Cytosine arabinoside;|
| Experimental: Dose Level 3<br>Mitoxantrone 8 mg/m2/day IV over 30 minutes once daily on days 1-5 Plerixafor 560 mcg/kg/day IV over 30 minutes on days 0-5 Etoposide 100 mg/m2/day IV over 60 minutes once daily on days 1-5 Cytarabine 1000 mg/m2/day IV over 60 minutes once daily on days 1-5 | Drug: Plerixafor<br> <br> * Other names: Mozobil;Drug: Mitoxantrone<br> <br> * Other names: Novantrone;Drug: Etoposide<br> <br> * Other names: VP156;Drug: Cytarabine<br> <br> * Other names: Cytosine arabinoside;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum tolerated dose and dose limiting toxicities of intravenous plerixafor when combined with MEC in patients with relapsed or refractory AML. |  | Days 1-42 (all patients have to complete) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the complete response rate (CR) for plerixafor when combined with MEC in patients with relapsed or refractory AML. |  | Between days 15-42 | 
| To determine the safety and tolerability of plerixafor in combination with MEC |  | Minimum of 30 days following completion of treatment | 
| To determine the PK and explore potential PK drug-drug interactions between plerixafor and MEC. |  | Predose, 15 min, 30 min , and 10 hrs | 
| To determine the time to hematologic recovery |  | For up to 2 years | 
| To characterize the mobilization of leukemic cells with plerixafor plus G-CSF. |  | Baseline, 6 hours | 
| To characterize the effects of plerixafor plus G-CSF on SDF-1/CXCR4 signaling on leukemic blasts. |  | Baseline, 6 hours | 
| To determine the time to overall survival |  | For up to 2 years | 
| To determine the time to event-free survival |  | For up to 2 years | 
| To determine the time to duration of remission |  | For up to 2 years | 
| To determine the time to relapse-free survival |  | For up to 2 years |