Neutropenia
Conditions
Keywords
neutropenia, myelokathexis, WHIM syndrome, AMD 3100, plerixafor, Myelokathexis syndrome, Neutropenia due to mutations of CXCR-4
Brief summary
This is an initial study to determine if CXCR4 inhibitor AMD 3100 or plerixafor may be a potential treatment for neutropenia due to CXCR4 mutations, the myelokathexis or WHIM (warts, hypogammaglobulinemia, immunodeficiency and myelokathexis) syndrome. This is the initial study of this concept and will involve up to 6 patients to receive increasing doses of plerixafor administered subcutaneously or on an alternate day basis. It is unknown if these patients will be highly sensitive to a blockade of CXCR4 activity and release more white blood cells than normal volunteers or cancer patients given the same dose of this drug. Therefore doses will begin at a level 12 fold less than currently used to mobilize stem cells and will be increased stepwise to achieve an acceptable circulating level of neutrophils.
Detailed description
This is an open label, single Center, phase I study to examine the hematological effects, pharmacokinetics and safety of plerixafor in patients with myelokathexis attributable to mutations of CXCR4, utilizing serial, escalating doses of plerixafor administered on days 1, 3, 5, 8, and 10. Five intrapatient escalating dose levels, 20 micrograms per kilogram (mcg/kg), 40 micrograms/kilogram(mcg/kg), 80 micrograms/kilogram(mcg/kg), and 240 micrograms/kilogram (mcg/kg)will be examined. The subjects will be patients at the University of Washington General Clinical Research Center for up to 10 days; the study requires subject be available for up to 14 days. Patients will be monitored for hematological effects of plerixafor and observed for adverse effects. If a normal blood neutrophil count is achieved and maintained for at least 24 hours prior to the highest dose, we will stop at that level.
Interventions
DRUGAMD3100 or plerixafor
The study will examine the hematological effects/safety of plerixafor in patients with myelokathexis attributable to mutations of CXCR4. Plerixafor will be administered on days 1, 3, 5, 8, and 10. Five intrapatient escalating doses of AMD 3100, 20 micrograms per kilogram (mcg/kg), 40 micrograms per kilogram (mcg/kg), 80 micrograms per kilogram (mcg/kg), and 240 micrograms per kilogram (mcg/kg) will be examined in the patients at University of Washington General Clinical Research Center for up to 10 days, requiring subjects be available up to 14 days. Patients will be monitored for hematological effects of plerixafor and observed for adverse effects. If normal blood neutrophil count is achieved and maintained for at least 24 hours prior to highest dose, we will stop at that level.
Sponsors
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* age over 18 years, WBC (white blood count) less than 3.0 x 10\^9 per Liter, * Absolute neutrophil count less than 2.0 x 10\^9 per Liter, * platelets greater than 100 x 10\^6 per Liter, creatinine less than 2.0/milligrams per/deciliter, * Creatinine clearance \> 60 ml/min calculated, * Aspartate Aminotransferase-GOT (SGOT), Alanin Aminotransferase-GPT (SGPT), bilirubin \< 2.5 upper limit of normal, * Eastern Cooperative Oncology Group (ECOG) status 0 or 1, * mutation identified and confirmed in CXCR4, * on no granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF) within 3 weeks of the study drug * patient signs consent, accepts contraception
Exclusion criteria
* greater than 18 years of age, * sensitivity to plerixafor, * pregnant, * prisoner, * decisionally impaired, * judged unlikely to comply, * illness that may interfere with interpretation of results, * leukemia, * malignancy, * active infection requiring antibiotics within one week of study drug administration, * history of cardiac conduction or electrocardiogram (EKG) abnormality, * previous experimental therapy within one week.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood Neutrophil Counts. | up to 14 days, depending on when subject reached peak response, i.e., the highest count after the stimulus (plerixafor) | Effectiveness of drug based on increases of blood neutrophil counts to greater than 2.0 x 10\^9 per liter |
Countries
United States
Participant flow
Recruitment details
Subjects were contacted from the Severe Chronic Neutropenia International Registry office by Audrey Anna Bolyard, Manager of the Registry.
Pre-assignment details
Prior to assignment, we performed physician, EKG (electrocardiogram) and screening labs, including CBC (complete blood count), Differential and smear, comprehensive metabolic panel, urinalysis, and pregnancy testing on females subjects
Participants by arm
| Arm | Count |
|---|---|
| Single Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor) Single arm study to examine the hematological effects, pharmacokinetics and safety of plerixafor in patients with myelokathexis attributable to mutations of CXCR4, utilizing serial, escalating doses of plerixafor administered on days 1, 3, 5, 8, and 10. Five intrapatient escalating dose levels, 20 micrograms per kilogram (mcg/kg), 40 micrograms/kilogram(mcg/kg), 80 micrograms/kilogram(mcg/kg), and 240 micrograms/kilogram (mcg/kg)will be examined. The subjects will be patients at the University of Washington General Clinical Research Center for up to 10 days; the study requires subject be available for up to 14 days. Patients will be monitored for hematological effects of plerixafor and observed for adverse effects. If a normal blood neutrophil count is achieved and maintained for at least 24 hours prior to the highest dose, we will stop at that level. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Single Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age Continuous | 42.7 years STANDARD_DEVIATION 17 |
| Blood neutrophil count (in myelokathexis) | 0.7 10^9 per Liter |
| blood neutrophil levels | 0.7 10^9 per Liter STANDARD_DEVIATION 0.6 |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
Blood Neutrophil Counts.
Effectiveness of drug based on increases of blood neutrophil counts to greater than 2.0 x 10\^9 per liter
Time frame: up to 14 days, depending on when subject reached peak response, i.e., the highest count after the stimulus (plerixafor)
Population: The number of participants (6) was determined by the fact that we were studying a rare form of neutropenia, WHIMS syndrome, and we therefore recruited subjects who have WHIMS who live on the West coast. Analysis was per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SINGLE Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor) | Blood Neutrophil Counts. | 4.48 10^9 per Liter | Standard Deviation 1.91 |
p-value: <0.05t-test, 2 sided
Comparison: The patients' leukocyte counts before and after plerixafor were compared.p-value: <0.05Ratio paired t-test