AMD 3100 for Treatment of Myelokathexis

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT01058993
• Collaborator: (none)
• Enrollment: 6
• Location: 1
• Arm: 1
• Duration (Months): 6
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Neutropenia	Drug: AMD3100 or plerixafor	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Study of the CXCR-4 Inhibitor AMD3100 for the Treatment of Neutropenia Due to Mutations of CXCR-4, the Myelokathexis Syndrome
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: AMD3100 or plerixafor SINGLE arm study with increasing doses of Plerixafor

Drug: AMD3100 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.; Other Names: Mozobil

Outcome Measures

Primary Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Washington Medical Center	Seattle	Washington	United States	98195

Sponsors and Collaborators

• University of Washington

Investigators

• Principal Investigator: David C Dale, MD, University of Washington

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: David Dale, Professor, University of Washington
• ClinicalTrials.gov Identifier: NCT01058993
• Other Study ID Numbers: 35419-D; MAMO-0407-1
• First Posted: Jan 29, 2010
• Last Update Posted: Jun 15, 2012
• Last Verified: May 1, 2012

• Keywords provided by David Dale, Professor, University of Washington: neutropenia; myelokathexis; WHIM syndrome; AMD 3100; plerixafor; Myelokathexis syndrome; Neutropenia due to mutations of CXCR-4
• Additional relevant MeSH terms: Neutropenia; Plerixafor

Study Results

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 Detail	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

Arm/Group Title	Single Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor)
Arm/Group Description	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.
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Single Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor)
Arm/Group Description	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.
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	6 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.7 (17.0)
Sex: Female, Male (Count of Participants)
Female	4 66.7%
Male	2 33.3%
Region of Enrollment (participants) [Number]
United States	6 100%
Blood neutrophil count (in myelokathexis) (10^9 per Liter) [Mean (Full Range) ]
Mean (Full Range) [10^9 per Liter]	0.7
blood neutrophil levels (10^9 per Liter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [10^9 per Liter]	0.7 (0.6)

Outcome Measures

1. Primary Outcome

Title	Blood Neutrophil Counts.
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	SINGLE Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor)
Arm/Group Description	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.
Measure Participants	6
Mean (Standard Deviation) [10^9 per Liter]	4.48 (1.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SINGLE Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments	Student t-test-comparison means of normal subjects & controls.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SINGLE Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor)
	Comments	The patients' leukocyte counts before and after plerixafor were compared.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Ratio paired t-test
	Comments	Ratio paired t-test for comparison of baselines and responses for each category of leukocytes

Adverse Events

Arm/Group Title	Single Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor)
Arm/Group Description	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.
All Cause Mortality
	Single Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Single Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor)
	Affected / at Risk (%)	# Events
Total	0/6 (0%)
Other (Not Including Serious) Adverse Events
	Single Arm Study, 5 Escalating Doses of AMD3100 (Plerixafor)
	Affected / at Risk (%)	# Events
Total	0/6 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.