Plerixafor and Granulocyte Colony-stimulating Factor (G-CSF) in Combination With Azacitidine for the Treatment of Myelodysplastic Syndrome (MDS) (MDS)

A Phase I Trial Evaluating the Effects of Plerixafor (AMD3100) and G-CSF in Combination With Azacitidine (Vidaza) for the Treatment of MDS

Our main objectives are to determine the optimal dose and schedule of plerixafor + G-CSF and azacitidine in patients with MDS and determine the safety and tolerability of plerixafor + G-CSF and azacitidine.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Plerixafor; Drug: G-CSF; Drug: Azacitidine

Detailed Description

The interaction of normal stem cells with the bone marrow microenvironment is mediated by a number of factors. These interactions have been implicated in protecting malignant hematopoietic cells from spontaneous apoptosis and genotoxic stresses such as chemotherapy. Key elements are CXCR4, which is expressed on normal stem cells and leukemic blasts, and its ligand, stromal derived factor 1 (SDF-1) expressed by bone marrow stromal cells and osteoblasts. The CXCR4/SDF-1 axis is essential for homing, retention and mobilization of stem cells from the bone marrow microenvironment. Plerixafor is a bicyclam small molecule inhibitor of CXCR4 and has been extensively studied by our group and others as a potent stem cell mobilization agent both in combination with G-CSF or alone (25, 62). Plerixafor is currently being investigated in a phase I/II trial in combination with salvage chemotherapy for relapsed AML in an attempt to sensitize leukemia stem cells to chemotherapy. The goal of this study is to determine the optimal dose of plerixafor for the treatment of patients with high-risk myelodysplastic syndrome (MDS) in combination with G-CSF and azacitidine. We hypothesize that plerixafor in combination with G-CSF will detach MDS blasts from the bone marrow microenvironment resulting in their increased proliferation and sensitivity to azacitidine; thus, improving complete and partial response rates (CR/PR).

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have histologically confirmed MDS with 5-20% blasts on bone marrow aspirate at the time of study enrollment AND at least one cytopenia.
• MDS is defined by the WHO criteria
• Previous therapy with decitabine or azacitidine will be allowed but patients must be at least 4 weeks from prior chemotherapy or radiation.
• Age >=18 years. Because no dosing or adverse event data are currently available on the use of plerixafor in combination with G-CSF or azacitidine in patients <18 years of age, children are excluded from this study; however, they will be eligible for future pediatric phase II combination trials.
• Life expectancy of greater than 2 months.
• ECOG performance status <= 2 (Karnofsky >=60%; see Appendix 1).
• Patients must have normal organ function as defined below:
• total bilirubin ≤ 1.5 X institutional upper limit of normal
• AST ≤ 2.0 X institutional upper limit of normal
• creatinine within normal institutional limits OR
• creatinine clearance >=60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
• Ability of the patient (or legally authorized representative, if applicable) to understand and the willingness to sign a written informed consent document.
• 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. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Exclusion Criteria:

• Patients with untreated 5q minus syndrome MDS
• Patients who have had G-CSF or GM-CSF within 2 weeks of the start of study
• Patients receiving any other investigational agents.
• Patients with known brain metastases. (These patients should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.)
• History of severe allergic or anaphylactic reactions attributed to compounds of similar chemical or biologic composition to plerixafor, azacitidine, G-CSF, or mannitol.
• History of sickle cell anemia. (G-CSF may initiate pain crises.)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because plerixafor, G-CSF, and azacitidine are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with azacitidine, G-CSF, or plerixafor, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study.
• Known HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with plerixafor. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
• Patients with advanced malignant hepatic tumors
• History of cardiac arrhythmia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Dose Level 1; AMD3100 320 μg/kg SC Days 1-5 of each 28 day cycle. Azacitidine 75 mg/m2 SC Days 1-5 of each 28 days cycle. G-CSF 5 μg/k SC Days 1-5 of each 28 days cycle.	Drug: Plerixafor; Other Names: Mozobil; Drug: G-CSF; Other Names: Filgrastim; Neupogen; Drug: Azacitidine; Other Names: Vidaza; 5-azacytidine
EXPERIMENTAL: Dose Level 2; AMD3100 440 μg/kg SC Days 1-5 of each 28 day cycle. Azacitidine 75 mg/m2 SC Days 1-5 of each 28 days cycle. G-CSF 5 μg/k SC Days 1-5 of each 28 days cycle.	Drug: Plerixafor; Other Names: Mozobil; Drug: G-CSF; Other Names: Filgrastim; Neupogen; Drug: Azacitidine; Other Names: Vidaza; 5-azacytidine
EXPERIMENTAL: Dose Level 3; AMD3100 560 μg/kg SC Days 1-5 of each 28 day cycle. Azacitidine 75 mg/m2 SC Days 1-5 of each 28 days cycle. G-CSF 5 μg/k SC Days 1-5 of each 28 days cycle.	Drug: Plerixafor; Other Names: Mozobil; Drug: G-CSF; Other Names: Filgrastim; Neupogen; Drug: Azacitidine; Other Names: Vidaza; 5-azacytidine
EXPERIMENTAL: Expanded DLT Cohort; After the MTD is determined, patients will be enrolled at the MTD dose of plerixafor. These patients will not receive G-CSF priming but will be treated with plerixafor and azacitidine for 2 cycles.	Drug: Plerixafor; Other Names: Mozobil; Drug: Azacitidine; Other Names: Vidaza; 5-azacytidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the optimal dose and schedule of plerixafor + G-CSF and azacitidine in patients with MDS	The observation period for bone marrow aplasia as a DLT will be 42 days after the start of the second cycle of treatment or until the documentation of progression to leukemia. For all other toxicities, the DLT observation period will be 28 days from the start of treatment.	42 days after the start of the second cycle of treatment
Determine the safety and tolerability of plerixafor + G-CSF and azacitidine		30 days post-treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Characterize the mobilization of MDS cells	Cycle 1 Day 5
Determine the pharmacokinetics of plerixafor on azacitidine	Cycle 1 Day 5
Determine progression free survival and response rates	2 years
Freedom from transfusion	2 years

Collaborators and Investigators

• Sponsor: Washington University School of Medicine

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 2, 2010
• Primary Completion (ACTUAL): July 1, 2014
• Study Completion (ACTUAL): October 18, 2016

Study Registration Dates

• First Submitted: February 5, 2010
• First Submitted That Met QC Criteria: February 8, 2010
• First Posted (ESTIMATE): February 9, 2010

Study Record Updates

• Last Update Posted (ACTUAL): March 20, 2017
• Last Update Submitted That Met QC Criteria: March 16, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine; Plerixafor
• Other Study ID Numbers: 10-0150 / 201101810

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No