Efficacy and Safety Study of Mavorixafor in Participants With Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) Syndrome

• ClinicalTrials.gov Identifier: NCT03995108
• Recruitment Status: Active, not recruiting
• First Posted: June 21, 2019
• Last Update Posted: October 6, 2021
• Sponsor: X4 Pharmaceuticals
• Information provided by (Responsible Party): X4 Pharmaceuticals

Study Description

Brief Summary:

This study has a double-blind, placebo-controlled Randomized Period and an Open-Label extension Period. The primary objective of the Randomized Period is to demonstrate the efficacy of mavorixafor in participants with WHIM syndrome as assessed by increasing levels of circulating neutrophils compared with placebo, and relative to a clinically meaningful threshold. The primary objective of the Open-Label Period is to evaluate the safety and tolerability of mavorixafor in participants with WHIM syndrome. Participants are allowed to continue treatment in the Open-Label extension Period, if regionally applicable, until mavorixafor becomes commercially available, or until the study is terminated by the Sponsor.

Condition or disease	Intervention/treatment	Phase
WHIM Syndrome	Drug: Mavorixafor; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Mavorixafor in Patients With WHIM Syndrome With Open-Label Extension
• Actual Study Start Date: October 17, 2019
• Estimated Primary Completion Date: September 2022
• Estimated Study Completion Date: October 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Mavorixafor; Participants (adults and adolescents [12 to 17 years of age weighing >50 kilograms [kg]) will receive mavorixafor 400 milligrams (mg) once daily (QD) orally for 52 weeks in the Randomized Period. Adolescents weighing ≤50 kg will receive mavorixafor 200 mg QD. Participants who complete the Randomized Period or are granted Early Release due to recurrent or significant infections, as adjudicated by a blinded, independent adjudication committee (AC), will be offered the opportunity to enroll in the Open-Label Period and receive treatment with mavorixafor 400 mg once daily orally until commercial availability or study termination by the Sponsor.	Drug: Mavorixafor; Mavorixafor provided as 100 mg capsules.; Other Name: AMD11070, X4P-001
Placebo Comparator: Placebo; Participants will receive placebo matching to mavorixafor QD orally for 52 weeks in the Randomized Period. Participants who complete the Randomized Period or are granted Early Release due to recurrent or significant infections, as adjudicated by a blinded, independent AC, will be offered the opportunity to enroll in the Open-Label Period and receive treatment with mavorixafor 400 mg once daily orally until commercial availability or study termination by the Sponsor.	Drug: Mavorixafor; Mavorixafor provided as 100 mg capsules.; Other Name: AMD11070, X4P-001; Drug: Placebo; Placebo matching to mavorixafor capsules

Outcome Measures

Primary Outcome Measures :

1. Randomized Period: Time (in Hours) Above Absolute Neutrophil Count (ANC) Threshold of 500 Cells/Microliter (µL) [ Time Frame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 min (each ± 5 min) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 min) post-dose at Baseline, Weeks 13, 26, 39, and 52 ]
2. Open-Label Period: Percentage of Participants With Adverse Events (AEs) [ Time Frame: From Day 1 (end of randomized period) up to end of study (30 days post-treatment in open-label period [Week 56 of open-label period]) ]

Secondary Outcome Measures :

1. Randomized Period: Area Under the Curve for ANC (AUCANC) Using Trapezoidal Method [ Time Frame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Baseline, Weeks 13, 26, 39, and 52 ]
2. Randomized Period: Infection Rate (Percentage of Participants With Infections) Based on Infections Adjudicated by a Blinded, Independent AC [ Time Frame: Baseline up to Week 52 ]
3. Randomized Period: Vaccine Titer Levels at Week 52 in Participants Vaccinated at Week 13, With Tetanus, Diphtheria, and Pertussis (Tdap) Including pertussis Toxin, and Tetanus [ Time Frame: Week 52 ]
4. Randomized Period: Vaccine Titer Levels at Week 52 for Human Papillomavirus (HPV) 16 and HPV 18 in Participants Receiving Vaccinations With HPV 9-Valent Vaccine, Recombinant (Gardasil®9) [ Time Frame: Week 52 ]
5. Randomized Period: Change From Baseline in Cutaneous Warts at Week 52, Based on Dermatologist Clinical Global Impression of Change (CGI-C) [ Time Frame: Baseline, Week 52 ]
6. Randomized Period: Time to Early Release as Confirmed by Blinded Independent AC [ Time Frame: Baseline up to Week 52 ]
7. Randomized Period: Percentage of Neutrophil Responders [ Time Frame: Baseline up to Week 52 ]
8. Randomized Period: Mavorixafor Treatment Group: AUCANC [ Time Frame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Baseline, Weeks 13, 26, 39, and 52 ]
9. Randomized Period: Time (in Hours) Above Absolute Lymphocyte Count (ALC) Threshold of 1000 Cells/µL [ Time Frame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Baseline, Weeks 13, 26, 39, and 52 ]
10. Randomized Period: Area Under the Curve for ALC (AUCALC) [ Time Frame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Baseline, Weeks 13, 26, 39, and 52 ]
11. Randomized Period: Percentage of Lymphocyte Responders [ Time Frame: Baseline up to Week 52 ]
12. Change From Baseline in Total ALC, Absolute Monocyte Count (AMC), ANC, and White Blood Cell (WBC) at Week 52 [ Time Frame: Baseline, Week 52 ]
13. Randomized Period: Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at Week 52 [ Time Frame: Baseline, Week 52 ]
14. Randomized Period: Infection Characteristics, The Number of Participants With Severe Infections [ Time Frame: Baseline up to Week 52 ]
15. Randomized Period: Infection Duration [ Time Frame: Baseline up to Week 52 ]
16. Randomized Period: Infection-Free Time [ Time Frame: Baseline up to Week 52 ]
17. Randomized Period: Number of Days Lost From Work/School [ Time Frame: Baseline up to Week 52 ]
18. Randomized Period: Quality of Life as Measured by 36-Item Short Form Survey Score [ Time Frame: Baseline up to Week 52 ]
19. Randomized Period: Quality of Life as Measured by Pediatric Quality of Life Inventory (PedsQL) Score [ Time Frame: Baseline up to Week 52 ]
20. Randomized Period: Quality of Life as Measured by EuroQoL-5 Dimension-5 Level (EQ-5D-5L) Score [ Time Frame: Baseline up to Week 52 ]
21. Randomized Period: Quality of Life as Measured by Life Quality Index (LQI) Score [ Time Frame: Baseline up to Week 52 ]
22. Randomized Period: Quality of Life as Measured by Dermatology LQI Score [ Time Frame: Baseline up to Week 52 ]
23. Randomized Period: Pharmacokinetics (PK), Maximum Observed Plasma Concentration (Cmax) of Mavorixafor [ Time Frame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Weeks 13, 26, 39, and 52; and 4 hours post-dose at Baseline ]
24. Randomized Period: PK, Time to Reach Cmax (Tmax) of Mavorixafor [ Time Frame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 min (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Weeks 13, 26, 39, and 52; and 4 hours post-dose at Baseline ]
25. Randomized Period: PK, Half-Life of (T1/2) of Mavorixafor [ Time Frame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Weeks 13, 26, 39, and 52; and 4 hours post-dose at Baseline ]
26. Randomized Period: PK, Area Under the Curve (AUC) of Mavorixafor [ Time Frame: Time 0 (pre-dose, up to 15 minutes prior), 30, 60, and 90 minutes (each ± 5 minutes) and 2, 3, 4, 8, 12, 16, and 24 hours (each ± 15 minutes) post-dose at Weeks 13, 26, 39, and 52; and 4 hours post-dose at Baseline ]
27. Open-Label Period: Vaccine Titer Levels During the First Year of Open-Label Period, in Participants Vaccinated With Tdap During the Study Including Pertusis Toxin and Tetanus [ Time Frame: Year 1 of open-label period ]
28. Open-Label Period: Vaccine Titer Levels During the First Year of the Open-Label Period for HPV 16 and HPV 18 in Participants Receiving Vaccinations With HPV 9-Valent Vaccine, Recombinant (Gardasil®9) During the Study [ Time Frame: Year 1 of open-label period ]
29. Open-Label Period: Change From Baseline in Cutaneous Warts at Week 52, Based on Dermatologist CGI-C [ Time Frame: Baseline, Week 52 of open-label period ]
30. Open-Label Period: Infection Rate (Percentage of Participants With Infections) Based on Infections Adjudicated by an AC [ Time Frame: Baseline up to Week 52 of open-label period ]

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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.
• Have a genotype-confirmed mutation of chemokine (C-X-C motif) receptor 4 (CXCR4) consistent with WHIM phenotype.
• Agree to use a highly effective form of contraception.
• Be willing and able to comply with the protocol.
• Have confirmed ANC ≤400 cells/µL during screening, obtained while participant has no clinical evidence of infection.

Inclusion Criteria for the Open-Label Period:

• Completed the Randomized Period; or
• Granted Early Release from the Randomized Period.

Exclusion Criteria:

• Has known systemic hypersensitivity to the mavorixafor drug substance, its inactive ingredients, or the placebo.
• Is pregnant or breastfeeding.
• Has any medical or personal condition, which 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.

Exclusion Criteria for the Open-Label Period:

• Participants who experience any treatment-limiting toxicity (TLT) will be excluded from participating in the Open-Label Period.

Contacts and Locations

Locations

United States, California

University of California San Diego Health/Rady Children's Hospital

San Diego, California, United States, 92123

California Dermatology Institute

Thousand Oaks, California, United States, 91320

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Maryland

Johns Hopkins University Medical Center

Baltimore, Maryland, United States, 21224

United States, Texas

University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390-9020

United States, Washington

University of Washington Medical Center

Seattle, Washington, United States, 98195

Australia, Queensland

Wesley Hospital

Auchenflower, Queensland, Australia, 4006

Children's Health Queensland Hospital

South Brisbane, Queensland, Australia, 4101

Austria

Medical University of Vienna - Medizinische Universität Wien

Wien, Austria, 1090

Denmark

Aarhus University Hospital

Aarhus, Denmark, 8000

France

CHU de Lyon, Institut d'Hematologie et d'Oncologie Pediatrique

Lyon, Rhne, France, 69008

CHU Paris Est, Hôpital d'Enfants Armand-Trousseau

Paris Cedex 12, France, 75571

Hopital Necker-Enfants Malades

Paris, France, 75743

Hungary

University of Debrecen, Affiliated Department of Infectology

Debrecen, Hajdu-Bihar, Hungary, H-4031

Israel

HaEmek Medical Center

Afula, Israel, 1834111

Italy

Università degli Studi di Brescia, Scienze Cliniche e Sperimentali

Brescia, Piazza Del Mercato, Italy, 25123

Korea, Republic of

Seoul National University Hospital, Children's Hospital

Seoul, Korea, Republic of, 03080

Netherlands

Emma Children's Hospital Academic Medical Center (AMC)

Amsterdam, Netherlands, 1105 AZ

Russian Federation

Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology

Moscow, Russian Federation, 117997

Academician I.P. Pavlov First Saint Petersburg State Medical University

Saint Pertersburg, Russian Federation, 197022

Spain

Hospital Sant Joan de Deu Barcelona

Barcelona, Esplugues De Llobregat, Spain, 8950

Hospital Universitario Virgen del Rocío

Seville, Sevilla, Spain, 41013

Turkey

Cukurova University Faculty of Medicine

Sarıcam, Adana, Turkey, 1330

Sponsors and Collaborators

X4 Pharmaceuticals

Investigators

• Study Director: Chief Medical Officer; X4 Pharmaceuticals

More Information

• Responsible Party: X4 Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03995108
• Other Study ID Numbers: X4P-001-103; 2019-001153-10 ( EudraCT Number ); 4WHIM ( Other Identifier: X4 Pharmaceuticals )
• First Posted: June 21, 2019
• Last Update Posted: October 6, 2021
• Last Verified: October 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Syndrome; Disease; Pathologic Processes