Phase 3 Randomized Double-Blind Study of Mavorixafor Versus Placebo in WHIM Syndrome Patients with Open-Label Extension

Trial ID: 2024-518461-10-00
Protocol: X4P-001-103
Sponsor: X4 Pharmaceuticals Inc.

Trial statistics

science

test molecules

location_city

research sites

public

countries

medical_information

disease

person_search

investigators

handshake

vendors

Diseases & Conditions

Immunodeficiency congenital

Objectives

The primary objective of this study is to demonstrate the efficacy of **mavorixafor** in participants with Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (**WHIM syndrome**) by assessing the increase in circulating neutrophils compared with placebo and relative to a clinically meaningful threshold. This is clinically relevant as it aims to address the underlying neutropenia associated with WHIM syndrome, potentially reducing the frequency and severity of infections and other complications.

Secondary objectives include: - Demonstrating the efficacy of mavorixafor in increasing levels of circulating lymphocytes compared with placebo and relative to a clinically meaningful threshold. - Assessing the clinical efficacy of mavorixafor through a composite endpoint of infections and warts. - Evaluating the improvement in warts and reduction in infections. - Evaluating the long-term efficacy of mavorixafor in participants with WHIM syndrome during the open-label period.

Participants

The clinical trial involves a total of **8 participants** diagnosed with **WHIM Syndrome** (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis). The study population includes both male and female subjects, with an age range starting from 12 years and above. Participants were selected based on a genotype-confirmed mutation of CXCR4 consistent with the WHIM phenotype. The trial includes individuals who are part of a vulnerable population, and all participants have agreed to use a highly effective form of contraception. The health status of participants is characterized by a confirmed absolute neutrophil count (ANC) of ≤ 400 cells/μL during screening, obtained while the participant has no clinical evidence of infection. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are willing and able to comply with the protocol requirements.

Plans and Procedures

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of **mavorixafor** in patients with WHIM Syndrome. The trial consists of two periods: a randomized placebo-controlled period and an open-label extension. The primary objective during the randomized period is to demonstrate the efficacy of mavorixafor by increasing levels of circulating neutrophils compared to placebo. The open-label period aims to assess the long-term safety and tolerability of mavorixafor.

The trial is expected to last until February 2026, with recruitment having started in October 2019. Participants will be involved for a maximum of 52 weeks during the randomized period, with the possibility of continuing into the open-label extension. The study includes several visits: an initial screening visit to confirm eligibility, regular follow-up visits every three months to assess primary and secondary endpoints, and an end-of-study visit to conclude participation. The primary endpoint for the randomized period is the time above threshold-absolute neutrophil count (TAT-ANC) of ≥ 500 cells/µL over a 24-hour period, assessed four times throughout the study. Secondary endpoints include time above threshold-absolute lymphocyte count (TAT-ALC) and composite clinical efficacy endpoints based on infection and wart scores.

Participants must meet specific inclusion criteria, such as being at least 12 years old, having a genotype-confirmed mutation of CXCR4 consistent with WHIM phenotype, and agreeing to use effective contraception. Conditions for early termination from the study include withdrawal of consent, non-compliance with the protocol, or adverse events that compromise participant safety. The trial is conducted under strict ethical guidelines, ensuring that all participants provide informed consent before enrollment.

Treatment

The clinical trial involves the administration of **Mavorixafor**, an investigational medicinal product, in patients diagnosed with Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome. **Mavorixafor** is provided in the form of a hard capsule, with each capsule containing the active chemical substance **mavorixafor**. The maximum daily dose is set at 400 mg, and the treatment period extends up to 52 weeks. The route of administration is oral, and the dosing schedule is designed to ensure consistent therapeutic levels of the drug. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in the randomized, double-blind, placebo-controlled phase of the trial. The placebo is designed to match the experimental product in appearance but does not contain the active substance. This allows for the assessment of the efficacy and safety of **Mavorixafor** by comparing outcomes between the treatment and placebo groups. The placebo is administered following the same oral route and dosing schedule as the active treatment to maintain blinding and ensure the integrity of the study results.

Efficacy

The efficacy of mavorixafor in the treatment of **Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome** will be assessed through a series of primary and secondary endpoints during a Phase 3, randomized, double-blind, placebo-controlled study. The primary endpoint for the randomized placebo-controlled period is the time above threshold-absolute neutrophil count (TAT-ANC) of ≥ 500 cells/μL over a 24-hour period, which will be assessed four times throughout the study, every three months for a total of 12 months, in the Intent-to-Treat (ITT) population.

Secondary endpoints during the randomized placebo-controlled period include the time above threshold-absolute lymphocyte count (TAT-ALC) of ≥ 1000 cells/μL over a 24-hour period, composite clinical efficacy endpoint based on total infection score and total wart change score, total wart change score based on central blinded, independent review of three target skin regions, and total infection score based on the number and severity of infections adjudicated by a blinded, independent Adjudication Committee (AC). In the open-label period, efficacy will be further evaluated by the proportion of neutrophil and lymphocyte responders, absolute and fold change from baseline for total ALC, AMC, ANC, and WBC count, and vaccine titer levels for Tdap and HPV 9-valent vaccine. Changes from baseline in cutaneous warts and total infection score will also be assessed. These parameters will be measured using validated laboratory tests and clinical evaluations to ensure accurate and reliable data collection and analysis.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Inclusion criteria for Randomized Period: 1. Be at least 12 years of age. 2. Have signed the current approved Informed Consent Form. Participants under 18 years of age (in the Netherlands and other applicable regions, participants under 16 years of age) will sign an approved informed assent form and must also have a signed parental/legal guardian consent. 3. Have a genotype-confirmed mutation of CXCR4 consistent with WHIM phenotype. 4. Agree to use a highly effective form of contraception, as detailed in Section 5.3.1. 5. Be willing and able to comply with this protocol. 6. Have a confirmed ANC ≤ 400 cells/μL during screening, obtained while participant has no clinical evidence of infection.
Inclusion criteria for Open-Label Period: 1. Completed the Randomized Placebo-Controlled Period. 2. Granted Early Release from the Randomized Placebo-Controlled Period. 3. Blind broken.

cancel

Exclusion Criteria

Exclusion criteria for Randomized Period: 1. Has known systemic hypersensitivity to the mavorixafor drug substance, its inactive ingredients, or the placebo. 2. Is pregnant or breastfeeding. 3. Has a known history of a positive serology or viral load for HIV or a known history of AIDS. 4. Has, at screening, laboratory tests meeting 1 or more of the following criteria: − A positive hepatitis C virus antibody with confirmation by hepatitis C virus ribonucleic acid polymerase chain reaction reflex testing. − A positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). − NOTE: If a participant tests negative for HBsAg, but positive for HBcAb, the participant would be considered eligible if the participant tests positive for hepatitis B surface antibody (also referred to as anti-HBsAg) on reflex testing. 5. Has, at screening, safety laboratory tests meeting 1 or more of the following criteria: − Hemoglobin < 8.0 g/dL − Platelets < 75,000 cells/μL − Estimated glomerular filtration rate based on the Modification of Diet in Renal Disease of ≤ 29 mL/min/1.73 m2 (Stage 4 or 5 chronic kidney disease) − Serum aspartate aminotransferase > 2.5 × ULN − Serum alanine aminotransferase > 2.5 × ULN − Total bilirubin > 1.5 × ULN (unless due to Gilbert’s syndrome, in which case total bilirubin ≥ 3.0 × ULN and direct bilirubin > 1.5 × ULN) 6. Had surgery requiring general anesthesia within the 4 weeks prior to Day 1. 7. Received any of the following treatments: − Plerixafor within 6 months prior to Day 1. − Chronic or prophylactic use of antibiotics (systemic or inhaled) within 4 weeks prior to Day 1. − Chronic or prophylactic use of G-CSF or granulocyte macrophage-colony stimulating factor within 2 weeks of Day 1. − Chronic or prophylactic use of systemic glucocorticoid use (> 5 mg prednisone equivalent per day) within 2 weeks prior to Day 1. − Any investigational therapy within 5 half-lives or 2 weeks prior to Day 1, whichever is longer. Prior use of any investigational therapies must be discussed with the Medical Monitor. 8. Is currently taking or has, within 2 weeks prior to Day 1, received any medication that is prohibited (see Section 6.4.1), based on potential for drug-drug interactions. 9. Has, at the planned initiation of study drug, a clinically diagnosed active infection (excluding warts) that has the potential to raise the ANC counts. 10. Has had a total splenectomy within 1 year. 11. Has a current diagnosis of myelofibrosis. 12. Has a medical history of hematological malignancies. 13. Has any other medical or personal condition that, in the opinion of the Investigator, may potentially compromise the safety or compliance of the participant or may preclude the participant’s successful completion of the clinical study. 14. Has corrected QT interval using Fridericia’s formula of > 450 ms.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Denmark	Not Recruiting	24 Oct 2019	1
France	Not Recruiting	24 Oct 2019	1
Italy	Not Recruiting	24 Oct 2019	1
The Netherlands	Not Recruiting	24 Oct 2019	—
Spain	Not Recruiting	24 Oct 2019	2
Netherlands	—	—	1