Clinical Trials /

Plerixafor Versus G-CSF in the Treatment of People With WHIM Syndrome

NCT02231879

Description:

Background: - WHIMS (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome) is a rare disease. It can cause cancers, infections, and warts. Researchers want to see if a drug called plerixafor can treat WHIMS. Objective: - To compare plerixafor versus granulocyte colony stimulating factor (G-CSF) for preventing infections in people with WHIMS. Eligibility: - People ages 10-75 with WHIMS who have a CXCR4 gene mutation. Design: - Participants will be screened with a medical history, physical exam, and blood and urine tests. They may have heart and spleen tests and body scans. They may have samples of skin or warts taken. Researchers may take photographs of warts. - Participants will start twice daily self-injections of G-CSF. Their doctors will decide the dosage. - Initial Period (4-12 weeks) - Participants will: - continue the injections and their usual antibiotics and/or immunoglobulin - have blood drawn - keep a daily health diary - Participants will visit the clinic for 2 days without injections. - Adjustment Period 1 (8 weeks): - Participants will: - continue twice daily injections from home - continue the daily health diary - have blood tests every 2 weeks. - Treatment Year 1: - Participants will - receive either plerixafor or G-CSF injections twice daily - continue the health diary - have blood tests every 2 months - visit the clinic about every 4 months - At the end of year 1, participants will visit the clinic for an evaluation. They will switch to the other study drug. They will have an 8-week adjustment and 1-year treatment period. - At the end of year 2, participants will visit the clinic to complete their injections and go back to their previous G-CSF regimen. Participants will continue their daily health diary and have blood tests for 5-6 months.

Related Conditions:
  • Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome (WHIMS)
Recruiting Status:

Active, not recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Plerixafor</span> Versus <span class="go-doc-concept go-doc-intervention">G-CSF</span> in the Treatment of People With WHIM Syndrome

Title

  • Brief Title: Plerixafor Versus G-CSF in the Treatment of People With WHIM Syndrome
  • Official Title: A Phase III Double-Blind Randomized Crossover Study of Plerixafor Versus G-CSF in the Treatment of Patients With WHIM Syndrome.
  • Clinical Trial IDs

    NCT ID: NCT02231879

    ORG ID: 140185

    NCI ID: 14-I-0185

    Trial Conditions

    Myelokathexis

    WHIMS

    Neutropenia

    Warts

    Trial Interventions

    Drug Synonyms Arms
    Plerixafor A to B, B to A
    G-CSF A to B, B to A

    Trial Purpose

    Background:

    - WHIMS (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome) is a rare
    disease. It can cause cancers, infections, and warts. Researchers want to see if a drug
    called plerixafor can treat WHIMS.

    Objective:

    - To compare plerixafor versus granulocyte colony stimulating factor (G-CSF) for preventing
    infections in people with WHIMS.

    Eligibility:

    - People ages 10 75 with WHIMS who have a CXCR4 gene mutation.

    Design:

    - Participants will be screened with a medical history, physical exam, and blood and
    urine tests. They may have heart and spleen tests and body scans. They may have samples
    of skin or warts taken. Researchers may take photographs of warts.

    - Participants will start twice daily self-injections of G-CSF. Their doctors will decide
    the dosage.

    - Initial Period (4 12 weeks)

    - Participants will:

    - continue the injections and their usual antibiotics and/or immunoglobulin

    - have blood drawn

    - keep a daily health diary

    - Participants will visit the clinic for 2 days without injections.

    - Adjustment Period 1 (8 weeks):

    - Participants will:

    - continue twice daily injections from home

    - continue the daily health diary

    - have blood tests every 2 weeks.

    - Treatment Year 1:

    - Participants will

    - receive either plerixafor or G-CSF injections twice daily

    - continue the health diary

    - have blood tests every 2 months

    - visit the clinic about every 4 months

    - At the end of year 1, participants will visit the clinic for an evaluation. They will
    switch to the other study drug. They will have an 8-week adjustment and 1-year
    treatment period.

    - At the end of year 2, participants will visit the clinic to complete their injections
    and go back to their previous G-CSF regimen. Participants will continue their daily
    health diary and have blood tests for 5 6 months.

    Detailed Description

    Warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WHIMS) is a rare
    combined primary immunodeficiency disorder caused by gain-of-function mutations in the gene
    for the chemokine receptor CXCR4. Normally, CXCR4 is expressed on most leukocyte subsets and
    functions in part to promote hematopoietic stem cell (HSC) and neutrophil homing to and
    retention in bone marrow. WHIM mutations alter the CXCR4 carboxyl terminus, which enhances
    and prolongs receptor signaling. As a result, egress of normally produced and functional
    neutrophils from the bone marrow to the blood is impaired causing neutropenia, a bone marrow
    pathologic finding referred to as myelokathexis. A similar mechanism may also affect other
    leukocyte subsets since WHIM patients usually are panleukopenic. Consequently, WHIM patients
    are predisposed to frequent acute bacterial infections, especially in the sinopulmonary
    tract, that may cause chronic morbidity, respiratory insufficiency and in some cases
    premature death. WHIM patients also have marked difficulty clearing infections with Human
    Papillomavirus (HPV), resulting in persistent cutaneous and anogenital warts that in several
    reported cases have evolved into cancer. Several deaths have also occurred due to cancer
    associated with Epstein -Barr virus (EBV) infection. Therapies currently used for WHIMS are
    non-specific and expensive, and include Granulocyte Colony-Stimulating Factor (G-CSF) (the
    drug currently approved by the Food and Drug Administration (FDA) to treat severe congenital
    neutropenia), intravenous immunoglobulin (IVIg), and prophylactic antibiotics. None of these
    measures has been formally evaluated for efficacy in WHIM syndrome (WHIMS); however, in our
    clinical experience based on the treatment of 24 WHIM patients seen at the National
    Institutes of Health (NIH) since 2006, recurrent bacterial infections continue to occur,
    despite the fact that the absolute neutrophil count (ANC) can be readily maintained above
    500 cells/microliter by G-CSF and IgG levels can be restored to the normal range by IVIg.
    Thus, there continues to be a major unmet medical need for effective therapy in WHIMS
    despite the availability and application of best therapy for neutropenia and
    hypogammaglobulinemia in these patients. Plerixafor (Mozobil ) is a specific small
    molecule antagonist of CXCR4, licensed by the FDA for HSC mobilization for transplantation
    in cancer, and is therefore a logical candidate for molecularly targeted treatment of WHIMS.
    The goal of treatment would be to reduce CXCR4 signaling to normal, not to zero, thus,
    absent any off-target effects, targeted chronic treatment with this agent may be safe. In
    this regard, 2 recent short term Phase I dose-escalation studies of plerixafor, one from our
    group, in a total of 9 patients demonstrated that the drug could safely mobilize not only
    neutrophils, but also all other leukocyte subsets that are decreased in the blood of WHIM
    patients. A follow-up Phase I study, conducted by our group, in 3 patients given plerixafor
    0.02-0.04 mg/kg/d for 6 months demonstrated that these hematopoietic effects were durable.
    Moreover, the frequency of infection was reduced on plerixafor as compared to retrospective
    data mined for the three years before starting therapy and prospective data collected for
    one year after ending therapy, even though 2 of the patients were taking GCSF during the
    comparison time periods. No new warts occurred during treatment and several existing warts
    improved or resolved. Although these results are encouraging, the small number of patients
    studied, limited duration of drug treatment, and retrospective mining of control data leave
    open to question whether plerixafor is truly efficacious for clinical outcomes in WHIMS. The
    randomized, double blinded, crossover trial described here is designed to answer this
    question by establishing the long-term safety and clinical efficacy (primary endpoint:
    infection severity; multiple secondary endpoints including wart control) of plerixafor as
    compared to G-CSF in the treatment of WHIMS patients 10-75 years of age. G-CSF as a
    comparator is required because of its approved use in patients with severe congenital
    neutropenia (SCN).

    Brief outline of study we intend to randomize 20 patients and treat them in a
    double-blinded manner for 1 year with G-CSF and 1 year with plerixafor using a crossover
    design to allow direct comparison of infection severity during treatment with both agents,
    at doses determined by the patient s individual neutrophil response. A schedule of events
    has been provided in Appendix A. Data will be analyzed as specified in the Statistics
    section (Section 14) after randomization. Tolerability and patient drug preference will also
    be assessed.

    Trial Arms

    Name Type Description Interventions
    A to B Other Crossover Double Blind Study: Subjects will start with one drug for one year and crossover to the other drug for the second year. Plerixafor, G-CSF
    B to A Other Crossover Double Blind Study: Subjects will start with one drug for one year and crossover to the other drug for the second year. Plerixafor, G-CSF

    Eligibility Criteria

    - INCLUSION CRITERIA:

    Subjects are eligible to enter the study if they meet all of the following criteria:

    1. Age greater than or equal to 10 and less than or equal to 75 years.

    2. Heterozygous mutation in the C-tail of CXCR4 in addition to a clinical diagnosis of
    WHIMS.

    3. Documented neutropenia with a baseline ANC below 1500 cells/microL of blood.

    4. History of severe and/or recurrent infections.

    5. Willingness to interrupt G-CSF medication, 2 days prior to study drug injection.

    6. Must have a local medical provider for medical management.

    7. Must be willing to provide blood, plasma, serum, and DNA samples for storage.

    8. Women of childbearing potential must agree to take appropriate steps to avoid
    becoming pregnant for the duration of the study. Participants in whom pregnancy is
    biologically possible must use at least 2 study approved methods of contraception,
    one of which must be a barrier method, and must continue contraception until 5 months
    after stopping the study drug:

    - Male or female condoms with a spermicide,

    - Diaphragm or cervical cap with spermicide,

    - Intrauterine device,

    - Contraceptive pills or patch, Norplant, Depo-Provera or other FDA-approved
    contraceptive,

    - Male partner with vasectomy and documented aspermatogenic sterility.

    9. Willingness to comply with the study medications, visits, and procedures, as deemed
    necessary by the principal investigator (PI).

    EXCLUSION CRITERIA:

    If any of the following exclusion criteria are met, a subject will not be enrolled in this
    study:

    1. Neutropenia due to maturation defects in the myeloid lineage or a type of
    neutropenia, which in the investigator s opinion, is unlikely to improve from the
    medication administered in this study.

    2. Pregnant or breast-feeding women.

    3. Known hypersensitivity to plerixafor, G-CSF, or any components of the products.

    4. Predisposition to or history of life-threatening cardiac arrhythmia.

    5. Requiring dialysis or having markedly impaired renal function with a Creatinine
    Clearance (CrCl) < 15 mL/min.

    6. Condition that in the investigator s opinion places a subject at undue risk by
    participating in the study.

    Minimum Eligible Age: 10 Years

    Maximum Eligible Age: 75 Years

    Eligible Gender: Both

    Primary Outcome Measures

    The primary endpoint is infection severity, which is measured as a composite of multiple weighted parameters according to rules defined in Appendix D of the protocol.

    Secondary Outcome Measures

    Component measures of infections; incidence and duration of infections, fevers, antibiotic treatments, and hospitalization.

    Control of warts as defined by at least a 50% reduction in numbers, areas or size of existing warts and number of new warts.

    Blood count and immunological parameters.

    Trial Keywords

    Infections

    Hypogammaglobulinemia

    CXCR4

    Myelokathexis

    Warts