A Phase I Study of Mozobil in the Treatment of Patients With WHIMS
| Status: | Recruiting |
|---|---|
| Conditions: | Other Indications |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 2/17/2019 |
| Start Date: | August 6, 2009 |
| End Date: | December 31, 2021 |
| Contact: | Elena J Cho |
| Email: | elena.cho@nih.gov |
| Phone: | (301) 761-7280 |
A Phase I Study of Mozobil (TM) in the Treatment of Patients With WHIMS
Background:
- WHIMS (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome) is caused
by various genetic changes that increase the activity of the chemokine receptor, CXCR4.
Excessive function of this receptor causes mature neutrophils (part of the white blood
cells) to be retained within the bone marrow rather than being released to the blood and
is one of the causes of severe inherited neutropenia (low white blood counts). In
neutropenia, the body is less able to fight off infection. Patients with WHIMS usually
are at risk for skin, soft tissue, sinus, and lung infections, which can result in loss
of hearing, teeth, and lung function.
- Current treatment for WHIMS consists of regular injections of a white blood cell growth
stimulating medication called granulocyte colony stimulating factor (G-CSF), and
supplemental immunoglobulin (antibody). These therapies are expensive, nonspecific, have
significant side effects and toxicities, and do not fully correct all problems,
especially warts and cancers related to human papillomavirus (HPV).
- A drug called Mozobil has been approved for use in combination with G-CSF to increase
the number of stem cells that can be collected prior to bone marrow transplantation.
Mozobil may offer a specific and well-tolerated new treatment for WHIMS and other
syndromes characterized by neutropenia.
Objectives:
- To evaluate whether Mozobil is safe and effective to treat neutropenia (low white blood
cell count) in patients with WHIMS.
- To determine an appropriate treatment dose of Mozobil, within currently approved dosage
levels.
Eligibility:
- Individuals between 18 and 75 years of age who have been diagnosed with WHIMS and have a
history of severe infections.
Design:
- Potential participants will undergo a screening with a medical history, physical
examination, questionnaire, heart and lung function scans, and blood and urine samples.
Tests will also be done for hepatitis B and C virus, and human immunodeficiency virus
(HIV) that causes acquired immunodeficiency syndrome (AIDS), as well as to check
neutrophil function.
- Patients who are being treated with G-CSF will stop injections for 2 days before being
admitted to the National Institutes of Health (NIH) Clinical Center.
- Patients may participate in a Dose Escalation study and receive increasing doses of
Mozobil over 5 days of treatment until their white blood cell count improves
sufficiently or the maximum approved dose is reached. Blood samples will be taken
regularly throughout the treatment process. Patients will then receive an additional
dose of Mozobil at the maximum approved dose or the dose sufficient to cause
improvement, before restarting the G-CSF injections.
- Patients may also participate in a long-term Chronic Dosing study and receive Mozobil
once or twice a day for up to a maximum of 60 months.
- WHIMS (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome) is caused
by various genetic changes that increase the activity of the chemokine receptor, CXCR4.
Excessive function of this receptor causes mature neutrophils (part of the white blood
cells) to be retained within the bone marrow rather than being released to the blood and
is one of the causes of severe inherited neutropenia (low white blood counts). In
neutropenia, the body is less able to fight off infection. Patients with WHIMS usually
are at risk for skin, soft tissue, sinus, and lung infections, which can result in loss
of hearing, teeth, and lung function.
- Current treatment for WHIMS consists of regular injections of a white blood cell growth
stimulating medication called granulocyte colony stimulating factor (G-CSF), and
supplemental immunoglobulin (antibody). These therapies are expensive, nonspecific, have
significant side effects and toxicities, and do not fully correct all problems,
especially warts and cancers related to human papillomavirus (HPV).
- A drug called Mozobil has been approved for use in combination with G-CSF to increase
the number of stem cells that can be collected prior to bone marrow transplantation.
Mozobil may offer a specific and well-tolerated new treatment for WHIMS and other
syndromes characterized by neutropenia.
Objectives:
- To evaluate whether Mozobil is safe and effective to treat neutropenia (low white blood
cell count) in patients with WHIMS.
- To determine an appropriate treatment dose of Mozobil, within currently approved dosage
levels.
Eligibility:
- Individuals between 18 and 75 years of age who have been diagnosed with WHIMS and have a
history of severe infections.
Design:
- Potential participants will undergo a screening with a medical history, physical
examination, questionnaire, heart and lung function scans, and blood and urine samples.
Tests will also be done for hepatitis B and C virus, and human immunodeficiency virus
(HIV) that causes acquired immunodeficiency syndrome (AIDS), as well as to check
neutrophil function.
- Patients who are being treated with G-CSF will stop injections for 2 days before being
admitted to the National Institutes of Health (NIH) Clinical Center.
- Patients may participate in a Dose Escalation study and receive increasing doses of
Mozobil over 5 days of treatment until their white blood cell count improves
sufficiently or the maximum approved dose is reached. Blood samples will be taken
regularly throughout the treatment process. Patients will then receive an additional
dose of Mozobil at the maximum approved dose or the dose sufficient to cause
improvement, before restarting the G-CSF injections.
- Patients may also participate in a long-term Chronic Dosing study and receive Mozobil
once or twice a day for up to a maximum of 60 months.
Mozobil (TM) (plerixafor injection, Genzyme Corp.) is a Food and Drug Administration approved
medication to mobilize CD34+ hematopoietic stem cells prior to apheresis and use in
autologous transplantation in non-Hodgkin lymphoma and multiple myeloma when used in
conjunction with granulocyte-colony stimulating factor (G-CSF). The drug s mechanism of
action is the specific and reversible inhibition of the chemokine receptor, CXCR4, expressed
on CD34+ cells and other leukocytes. This inhibition interferes with the binding of stromal
cell derived factor-1 (SDF-1), which is constitutively expressed on bone marrow stromal cells
and appears to cause direct and indirect cellular adhesive interactions. Severe congenital
neutropenia is a rare inherited disorder in which the affected individuals develop chronic or
cyclical neutropenia with circulating counts below 500 cells/microliter blood. This disorder
may result from a variety of genetic defects in progenitor- or neutrophil-expressed genes
such as elastase, CXCR4, G6PC3, etc. Myelokathexis is the abnormal retention of mature
leukocytes in the bone marrow and is seen in some types of severe chronic neutropenia such as
warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WHIMS). WHIMS is a rare
primary immunodeficiency, which is known to be caused by mutations that enhance CXCR4
signaling. Our hypothesis is that Mozobil(TM) can be used safely to partially block CXCR4 and
treat neutropenia resulting from myelokathexis at doses considerably lower than that being
used for CD34+ cell mobilization. This new treatment could also improve other aspects of the
disease such as frequent infections, warts, and hypogammaglobulinemia. To test this
hypothesis, we propose this trial of Mozobil (TM) in adults with WHIMS, examining safety and
absolute neutrophil count as the primary endpoint.
medication to mobilize CD34+ hematopoietic stem cells prior to apheresis and use in
autologous transplantation in non-Hodgkin lymphoma and multiple myeloma when used in
conjunction with granulocyte-colony stimulating factor (G-CSF). The drug s mechanism of
action is the specific and reversible inhibition of the chemokine receptor, CXCR4, expressed
on CD34+ cells and other leukocytes. This inhibition interferes with the binding of stromal
cell derived factor-1 (SDF-1), which is constitutively expressed on bone marrow stromal cells
and appears to cause direct and indirect cellular adhesive interactions. Severe congenital
neutropenia is a rare inherited disorder in which the affected individuals develop chronic or
cyclical neutropenia with circulating counts below 500 cells/microliter blood. This disorder
may result from a variety of genetic defects in progenitor- or neutrophil-expressed genes
such as elastase, CXCR4, G6PC3, etc. Myelokathexis is the abnormal retention of mature
leukocytes in the bone marrow and is seen in some types of severe chronic neutropenia such as
warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WHIMS). WHIMS is a rare
primary immunodeficiency, which is known to be caused by mutations that enhance CXCR4
signaling. Our hypothesis is that Mozobil(TM) can be used safely to partially block CXCR4 and
treat neutropenia resulting from myelokathexis at doses considerably lower than that being
used for CD34+ cell mobilization. This new treatment could also improve other aspects of the
disease such as frequent infections, warts, and hypogammaglobulinemia. To test this
hypothesis, we propose this trial of Mozobil (TM) in adults with WHIMS, examining safety and
absolute neutrophil count as the primary endpoint.
- INCLUSION CRITERIA:
All of the following inclusion criteria must be met for a subject to be enrolled in this
study:
- Clinical diagnosis of WHIMS and documented severe infection
- Must be greater than or equal to 18 and less than or equal to 75 years of age
- Willingness to interrupt medications to raise the white count (WBC) such as G-CSF or
GM-CSF for at least 1 week before and while on the study drug
- Willingness to interrupt treatment with intravenous immunoglobulins (IVIG) while on
the study drug.
- Must not be pregnant or breastfeeding
- Must have a personal physician
- Must be willing to provide blood, plasma, serum, and DNA samples for storage
- Subjects must agree not to become pregnant or to impregnate a female. If of
childbearing potential, must agree to consistently use two types of contraception
throughout study participation. Acceptable forms of contraception include the
following:
1. Condoms, male or female, with or without a spermicide
2. Diaphragm or cervical cap with spermicide
3. Intrauterine device
4. Contraceptive pills or patch, Norplant, Depo-Provera or other FDA-approved
contraceptive method
5. Male partner has previously undergone a vasectomy for which there is
documentation of aspermatogenic sterility
EXCLUSION CRITERIA:
If any of the following exclusion criteria are met, a subject will not be enrolled in this
study:
- Absence of a diagnosis of WHIMS
- Patient is less than 18 years old
- Absence of a documented history of severe infection
- Neutropenia due to maturation defects in the myeloid lineage or that the PI feels is
unlikely to benefit from this medication
- Pregnant women or breastfeeding
- History of serious cardiac arrhythmia or cardiac defects that make such more likely
- Renal failure (calculated creatinine clearance [CrCl] <15 mL/min or requiring
dialysis)
- Signs or symptoms of active microbial infection
- Any condition that, in the investigator s opinion, places the patient at undue risk by
participating in the study
- Unwillingness to undergo testing or procedures associated with this protocol
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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