Chemosensitization With Plerixafor Plus G-CSF in Acute Myeloid Leukemia

Phase 1

Completed

• Conditions: Leukemia, Myeloid, Acute
• Interventions: Drug: G-CSF; Drug: Plerixafor; Drug: Mitoxantrone; Drug: Etoposide; Drug: Cytarabine

• Registration Number: NCT00906945
• Lead Sponsor: Washington University School of Medicine

Brief Summary

This study is designed to test the combination of Plerixafor with G-CSF for chemosensitization in patients with relapsed or refractory AML.

Detailed Description

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 this study, we seek to maximize blockage of the SDF-1/CXCR4 axis through the following:

1. Addition of G-CSF, which down regulates SDF-1 expression and acts synergistically with plerixafor in stem cell mobilization

2. Intravenous instead of subcutaneous dosing of plerixafor to improve kinetics of administration.

3. Dose escalation of plerixafor and twice daily dosing to maintain maximum CXCR4 blockade.

Study Timeline

• Study First Submitted: 2009-05-13
• Study First Submitted QC: 2009-05-20
• Study First Posted: 2009-05-21
• Study Start: 2011-02
• Primary Completion: 2012-11
• Study Completion: 2015-09
• Results First Submitted: 2016-12-20
• Status Verified: 2017-02
• Results First Submitted QC: 2017-02-14
• Last Update Submitted: 2017-02-14
• Results First Posted: 2017-04-04
• Last Update Posted: 2017-04-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 39

Inclusion Criteria

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

   • Primary refractory disease following no more than 2 cycles of induction chemotherapy
   • First relapse with no prior unsuccessful salvage chemotherapy

2. Age between 18 and 70 years old

3. ECOG performance status ≤ 3

4. Adequate organ function defined as:

   • Calculated creatinine clearance ≥ 50 ml/min
   • AST, ALT, total bilirubin ≤ 2 x ULN except when in the opinion of treating physician is due to direct involvement of leukemia (eg. hepatic infiltration or biliary obstruction due to leukemia)
   • Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram

5. Are surgically or biologically sterile or willing to practice acceptable birth control, as follows:

   • Females of child bearing potential must agree to abstain from sexual activity or to use a medically approved contraceptive measure/regimen during and for 3 months after the treatment period. Women of child bearing potential must have a negative serum or urine pregnancy test at the time of enrollment. Acceptable methods of birth control include oral contraceptive, intrauterine device (IUD), transdermal/implanted or injected contraceptives and abstinence.
   • Males must agree to abstain from sexual activity or agree to utilize a medically approved contraception method during and for 3 months after the treatment period

6. 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. Received any other investigational agent or cytotoxic chemotherapy (excluding hydroxyurea) within the preceding 2 weeks
7. Received colony stimulating factors filgrastim or sargramostim within 1 week or pegfilgrastim within 2 weeks of study
8. Severe concurrent illness that would limit compliance with study requirements

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dose Level 2	Cytarabine	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 320 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 1	G-CSF	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 240 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 1	Etoposide	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 240 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 3	Etoposide	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 420 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 3	Cytarabine	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 420 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 1	Plerixafor	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 240 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 2	G-CSF	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 320 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
MTD - Phase II	Cytarabine	* G-CSF MTD determined in Phase 1 SQ on Days 1-8 * Plerixafor MTD determined in Phase 1 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 2	Etoposide	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 320 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 4	G-CSF	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 560 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 4	Plerixafor	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 560 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 1	Mitoxantrone	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 240 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 2	Mitoxantrone	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 320 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 1	Cytarabine	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 240 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 2	Plerixafor	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 320 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 3	G-CSF	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 420 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 3	Plerixafor	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 420 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 3	Mitoxantrone	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 420 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 4	Mitoxantrone	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 560 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 4	Cytarabine	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 560 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 4	Etoposide	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 560 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 5	Plerixafor	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 750 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 5	G-CSF	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 750 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 5	Etoposide	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 750 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 5	Cytarabine	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 750 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
Dose Level 5	Mitoxantrone	* G-CSF 10 mcg/kg SQ on Days 1-8 * Plerixafor 750 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
MTD - Phase II	G-CSF	* G-CSF MTD determined in Phase 1 SQ on Days 1-8 * Plerixafor MTD determined in Phase 1 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
MTD - Phase II	Plerixafor	* G-CSF MTD determined in Phase 1 SQ on Days 1-8 * Plerixafor MTD determined in Phase 1 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
MTD - Phase II	Mitoxantrone	* G-CSF MTD determined in Phase 1 SQ on Days 1-8 * Plerixafor MTD determined in Phase 1 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8
MTD - Phase II	Etoposide	* G-CSF MTD determined in Phase 1 SQ on Days 1-8 * Plerixafor MTD determined in Phase 1 mcg/kg/d IV qd * Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8 * Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8 * Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8

Primary Outcome Measures

Name	Time	Method
Phase I: Maximum Tolerated Dose of Plerixafor Plus G-CSF When Combined With MEC	Completion of Phase I enrollment (17 months)
Phase II: Complete Response Rate (CR+CRi)	45 days	* Morphologic complete remission (CR): Defined as morphologic leukemia-free state, including \<5% blasts in BM aspirate with marrow spicules and a count of \> 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC \> 1,000/mm3, platelet count \> 100,000/mm3.; * Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia \<1,000/mm3 or thrombocytopenia \<100,000/mm3.

Secondary Outcome Measures

Name	Time	Method
Time to Hematologic Recovery as Measured by Time to Platelet Recovery	Up to 62 days after treatment	-Platelet recovery is defined as platelets \>= 100,000/mm3
Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in White Blood Cells	6 hours after plerixafor
Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 1D9 Relative Mean Fluorescent Intensity	6 hours after plerixafor
Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 12G5 Relative Mean Fluorescent Intensity	6 hours after plerixafor
Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency	30 days following end of treatment
Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery	Up to 62 days after treatment	-Neutrophil recovery is defined as absolute neutrophil count \>= 1000/mm\^3
Time to Progression	2 years	Recurrence / morphologic relapse: Defined as reappearance of blasts in the blood or the finding of \> 5% blasts in the BM, not attributable to any other cause. New dysplastic changes are considered a relapse. If there are no blasts in the peripheral blood and 5-19% blasts in the BM, the BM biopsy and aspirate should be repeated in \> 1 week to confirm relapse.
Time to Treatment Failure	8 days
Overall Survival	Median follow-up was 34.6 months	Overall survival: Defined as the date of first dose of study drug to the date of death from any cause.
Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in AML Blast Count	6 hours after plerixafor

Trial Locations

Locations (3)

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Washington University; 🇺🇸 St. Louis, Missouri, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States