A treatment study in patients with WHIM Syndrome.

• Register: EUCTR
• Last refreshed on: 2 March 2022
• Main ID: EUCTR2019-001153-10-PL
• Date of registration: 09/03/2020
• Prospective Registration: Yes
• Primary sponsor: X4 Pharmaceuticals Incorporated
• Public title: A treatment study in patients with WHIM Syndrome.
• Scientific title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Mavorixafor in Patients with WHIM Syndrome with Open-Label Extension - A treatment study in patients with WHIM Syndrome.
• Date of first enrolment: 27/04/2020
• Target sample size: 28
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-001153-10
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Canada, Denmark, France, Germany, Hungary, Israel, Italy, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, Turkey, United Kingdom, United States

Contacts

• Name: Sarah Cohen
• Affiliation: X4 Pharmaceuticals Incorporated

• Name: Sarah Cohen
• Affiliation: X4 Pharmaceuticals Incorporated

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion criteria for Randomized Period:

1. Be at least 12 years of age and Tanner stage =3.

2. Have signed the current approved informed consent form. Patients under 18 years of age (in
the Netherlands and other applicable regions, patients 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.

5. Be willing and able to comply with this protocol.

6. Have a confirmed ANC =400 cells/µL during screening. Baseline must be obtained while patient has no clinical evidence of infection. If the ANC value reflects subclinical infection, it may be repeated prior to randomization.

Inclusion criteria for Open-Label Period:
1. Completed the Randomized Period.
2. Granted Early Release from the Randomized Period.
Are the trial subjects under 18? yes
Number of subjects for this age range: 5
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 23
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 nursing.

3. Has inadequately controlled diabetes (hemoglobin A1C >7%).

4. Has a known history of a positive serology or viral load for human immunodeficiency virus or a known history of acquired immune deficiency syndrome.

5. Has, at screening, laboratory tests meeting one or more of the following criteria:
- A positive hepatitis C virus antibody (HCVAb) 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 patient tests negative for HBsAg, but positive for HBcAb, the patient would be considered eligible if the patient tests positive for hepatitis B surface antibody (HBsAb, also referred to as anti-HBsAg) on reflex testing.

6. Has, at screening, safety laboratory tests meeting one 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 >2.5x the upper limit of normal (ULN)
- Serum alanine aminotransferase >2.5x ULN
- Total bilirubin >1.5x ULN (unless due to Gilbert’s syndrome, in which case total bilirubin =3.0x ULN and direct bilirubin >1.5x ULN)

7. Had surgery requiring general anesthesia within the 4 weeks prior to Day 1.

8. Received any of the following treatments:
- Plerixafor within 18 months prior to Day 1.
- Chronic or prophylactic use of antibiotics (systemic or inhaled) within 4 weeks prior to Day 1.
- Granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor within 2 weeks of Day 1.
- Ig (intravenous or subcutaneous) within 5 months of study entry, unless deemed necessary by the treating physician and after agreement from the Sponsor. Provision is made for a stratum for patients using prophylactic Ig within 5 months of study entry (capped at 30% of the overall patient count).
- 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 investigational therapies must be discussed with the Medical Monitor.

9. Has, within 2 weeks prior to Day 1, received any medication that is a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein.

10. Has, at the planned initiation of study drug, a clinically diagnosed active infection (excluding
warts).

11. Has had a splenectomy.

12. Has a current diagnosis of myelofibrosis.

13. Has a medical history of hematological malignancies.

14. Has any other medical or personal condition, which in the opinion of the Investigator may
potentially compromise the safety or compliance of the patient or may preclude the patient’s successful completion of the clinical study.

Exclusion criteria for Open-Label Period:

1.Patients who experience any treatment-limiting toxicity (TLT) during the first 4 weeks of treatment or any critical TLT at any time.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

WHIM Syndrome

Therapeutic area: Body processes [G] - Immune system processes [G12]

Intervention(s)

Product Name: Mavorixafor
Product Code: X4P-001
Pharmaceutical Form: Capsule
INN or Proposed INN: Mavorixafor
CAS Number: 558447-26-0
Current Sponsor code: X4P-001
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: Primary Objective for Randomized Period: To demonstrate the efficacy of mavorixafor in patients with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome as assessed by increasing levels of circulating neutrophils compared with placebo, and relative to a clinically meaningful threshold.

Primary Objective for Open-Label Period. To evaluate the safety and tolerability of mavorixafor in patients with WHIM syndrome.

Primary end point(s): Primary endpoint in Randomized Period: Time (in hours) above ANC threshold of 500 cells/µL over a 24-hour period, assessed 4 times through the study (every 3 months).

Primary Endpoint in Open-Label Period: Safety and tolerability of mavorixafor in patients with WHIM syndrome, as assessed by AEs, clinical laboratory evaluations, vital signs, ECG assessments, and physical and ophthalmologic examinations.

Secondary Objective: Secondary Objective for Randomized Period:
1.To evaluate the safety and tolerability of mavorixafor in patients with WHIM
syndrome.

2.To evaluate the efficacy of mavorixafor in patients with WHIM syndrome as assessed
by clinical outcomes (e.g., rate of infections, incidence of protective vaccine titers,
and impression of change in wart burden).

Secondary Objective for Open-Label Period: To evaluate the efficacy of mavorixafor in patients with WHIM syndrome.

Timepoint(s) of evaluation of this end point: The primary endpoint analysis will compare the difference between mavorixafor and placebo
with respect to the mean time above ANC threshold using MMRM analysis in the ITT Population. Time (in hours) above threshold will be calculated using a linear interpolation, such that the time between intervals where ANC values cross the threshold will be determined based on the slope between the 2 timepoints.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Key secondary efficacy endpoints represent objectively defined, verifiable clinical outcomes. A
hierarchical approach to formal statistical testing will be used, with the hierarchy planned in the
order of presentation of secondary endpoints in Section 3.2.1. The ITT Population is the primary
population for analysis. The 24-hour AUCANC will be calculated using the trapezoidal method and compared between treatment groups using similar methods as the primary endpoint.

Secondary end point(s): The key secondary endpoints for Randomized period are:
1.AUCANC over 24 hours, calculated using the trapezoidal method

2.Infection rate based on infections adjudicated by a blinded, independent adjudication committee.
Incidence of protective vaccine titers at Week 52 in patients vaccinated at Week 13, including pertussis toxin, HPV 16, HPV 18, and tetanus titers.

3.Change from baseline in cutaneous warts, based on dermatologist Clinical Global
Impression of Change.

4. Proportion of neutrophil responders, defined as patients with ANC above the 500 cells/µL threshold at least 50% of the time as well as ANC above threshold for the entire 24-hour period.

5. AUCANC over 24 hours, to be assessed by a within-group comparison to the clinicallymeaningful threshold of =500 cells/µL in the mavorixafor treatment group (where the 24-hour threshold AUC is calculated as 500 × 24).

6. Time (in hours) above ALC threshold over a 24-hour period, where the threshold is
defined as 1000 cells/µL

7. AUCALC over 24 hours, calculated using the trapezoidal method

8. Proportion of lymphocyte responders, defined as patients with baseline ALC below the lower limit of normal who achieve on-treatment ALC above the 1000 cells/µL threshold at least 50% of the time as well as ALC above threshold for the entire 24-hour period.

9. Infection duration

10.Infection characteristics (e.g., type of infection, duration of treatment, severity)

11. Infection-free time

12. Number of days lost from work/school

13. QoL

14.PK of mavorixafor in WHIM patients =12 years of age

The secondary efficacy endpoints for Open Label:

1. Incidence of protective vaccine titers at Week 13 of the Open-Label Period, in patients vaccinated at Week 13 of the Randomized Period, including pertussis toxin, HPV 16, HPV 18, and tetanus titers.

2. Change from baseline in cutaneous warts, based on dermatologist Clinical Global
Impression of Change

3. Incidence of infection

Secondary ID(s)

2019-001153-10-FR

X4P-001-103

NCT03995108

129092

Source(s) of Monetary Support

X4 Pharmaceuticals Incorporated

Ethics review

Status: Approved
Approval date: 01/04/2020
Contact: