A Study of Axatilimab at 3 Different Doses in Participants With Chronic Graft Versus Host Disease (cGVHD)

Official title

AGAVE-201, A Phase 2, Open-label, Randomized, Multicenter Study to Evaluate the Efficacy, Safety and Tolerability of Axatilimab at 3 Different Doses in Patients With Recurrent or Refractory Active Chronic Graft Versus Host Disease Who Have Received at Least 2 Lines of Systemic Therapy

Overview

This is a Phase 2 study to evaluate the efficacy, safety, and tolerability of axatilimab at 3 different dose levels in participants with recurrent or refractory active chronic graft versus host disease (cGVHD) who have received at least 2 prior lines of systemic therapy.

Detailed description

AGAVE-201 is a Phase 2, open-label, randomized, multicenter study to evaluate the efficacy, safety, and tolerability of axatilimab in participants with recurrent or refractory active cGVHD after failure of at least 2 prior lines of systemic therapy due to progression of disease, intolerability, or toxicity.

Participants will be randomized to receive 1 of 3 different axatilimab treatment regimens in 28-day treatment cycles for up to 2 years.

Interventions

• Drug Axatilimab
  Axatilimab is a high-affinity antibody targeting the colony stimulating factor 1 receptor (CSF-1R). CSF-1R signaling has been demonstrated in nonclinical studies to be the key regulatory pathway involved in the expansion and infiltration of donor-derived macrophages that mediate the disease processes involved in cGVHD.

Primary outcome measures

• Overall Response Rate (ORR) in the First 6 Cycles as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease (cGVHD) [Time frame: First 6 cycles (up to Cycle 7 Day 1; each cycle = 4 weeks)]

Secondary outcome measures (12)

• ORR on Study as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD [Time frame: Up to 2 years]
• Number of Participants With a Clinically Significant Improvement in Normalized Score on the Modified Lee Symptom Scale [Time frame: Up to 2 years]
• Duration of Response [Time frame: Up to 2 years]
• Sustained Response Rate [Time frame: Up to 2 years]
• Organ-specific Response Rate [Time frame: Up to 2 years]
• Joints and Fascia Response Rate Based on Refined NIH Response Algorithm for cGVHD [Time frame: Up to 2 years]
• Percent Reductions in Average Daily Doses (or Equivalent) of Corticosteroid [Time frame: Up to 2 years]
• Number of Participants Who Discontinue Corticosteroid Use [Time frame: Up to 2 years]
• Percent Reductions in Average Daily Doses (or Equivalent) of Calcineurin Inhibitors (CNI) [Time frame: Up to 2 years]
• Number of Participants Who Discontinue CNIs [Time frame: Up to 2 years]
• Change From Baseline in Circulating Monocyte Number and Phenotype (CD14/16) [Time frame: Baseline, up to 2 years]
• Number of Participants With Anti-Drug Antibody [Time frame: Up to 2 years]

Eligibility criteria

Inclusion criteria

• Participants must be 2 years of age or older, at the time of signing the informed consent.
• Participants who are allogeneic hematopoietic stem cell transplantation (HSCT) recipients with active cGVHD requiring systemic immune suppression. Active cGVHD is defined as the presence of signs and symptoms of cGVHD per 2014 NIH Consensus Development Project on Criteria for Clinical trials in cGVHD.
• Participants with refractory or recurrent active cGVHD despite at least 2 lines of systemic therapy.

• Refractory disease defined as meeting any of the following criteria:

• The development of 1 or more new sites of disease while being treated for cGVHD.
• Progression of existing sites of disease despite at least 1 month of standard or investigation therapy for cGVHD.
• Participants who have not achieved a response within 3 months on their prior therapy for cGVHD and for whom the treating physician believes a new systemic therapy is required.
• Recurrent cGVHD is active, symptomatic disease (after an initial response to prior therapy) as defined, based on the NIH 2014 consensus criteria, by organ-specific or global assessment or for which the physician believes that a new line of systemic therapy is required.
• Participants may have persistent, active acute and cGVHD manifestations (overlap syndrome), as defined by 2014 NIH Consensus Development Project on Criteria for Clinical trials in cGVHD.
• Karnofsky Performance Scale of ≥60 (if aged 16 years or older); Lansky Performance Score of ≥60 (if aged <16 years)
• Adequate organ and bone marrow functions evaluated during the 14 days prior to randomization.
• Creatinine clearance (CrCl) ≥30 milliliter/minute based on the Cockcroft-Gault formula in adult participants and Schwartz formula in pediatric participants.
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Concomitant use a of systemic corticosteroid is allowed but not required. Topical and inhaled corticosteroid agents are allowed. If a participant is taking corticosteroids at study randomization, they must be on a stable dose of corticosteroids for at least 2 weeks prior to Cycle 1 Day 1.
• Concomitant use of CNI or mammalian target of repamycin (mTOR) inhibitors (sirolimus or everolimus) is allowed but not required.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol. A parent/guardian should provide consent for pediatric participants unable to provide consent themselves; in addition, where applicable pediatric participants should sign their own assent form.

Exclusion criteria

Participants are excluded from the study if any of the following criteria apply:

• Has acute GVHD without manifestations of cGVHD.
• Any evidence (histologic, cytogenetic, molecular, hematologic, or mixed) of relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time of screening.
• History of acute or chronic pancreatitis.
• History of myositis.
• History or other evidence of severe illness, uncontrolled infection or any other conditions that would make the participant, in the opinion of the Investigator, unsuitable for the study.
• Participants with acquired immune deficiency syndrome (AIDS).
• Hepatitis B (defined as hepatitis B virus \[HBV\] surface antigen positive and HBV core antibody positive, with positive HBV deoxyribonucleic acid \[DNA\], or HBV positive core antibody alone with positive HBV DNA. Hepatitis C (defined as positive hepatitis C \[HCV\] antibody with positive HCV ribonucleic acid \[RNA\]).
• Diagnosed with another malignancy (other than malignancy for which transplant was performed) within 3 years of randomization, unless previously treated with curative intent and approved by Sponsor's Medical Monitor (for example, completely resected basal cell or squamous cell carcinoma of the skin, resected in situ cervical malignancy, resected breast ductal carcinoma in situ, or low-risk prostate cancer after curative resection).
• Female participant who is pregnant or breastfeeding.
• Previous exposure to CSF1-R targeted therapies.
• Taking agents for treatment of cGVHD other than corticosteroids or either a CNI or mTOR inhibitor is prohibited.
• For approved or commonly used agents, other than corticosteroids, CNI and mTOR inhibitor, a washout of 2 weeks or 5 half-lives, whichever is shorter, is required at study enrollment.
• Receiving another investigational treatment within 28 days of randomization.
• Participants should not be participating in any other interventional study. Pediatric participants are encouraged to also participate in the ongoing developmental studies of the Pediatric cGVHD Symptom Scale (PCSS).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 47 centers

• University of Alabama at Birmingham - Children's of Alabama — Birmingham
• University of Alabama at Birmingham — Birmingham
• City of Hope — Duarte
• University of Southern California Norris Comprehensive Cancer Center — Los Angeles
• University of California, Los Angeles (UCLA) - Medical Center — Los Angeles
• Stanford Cancer Center — Stanford
• Children's National Medical Center — Washington D.C.
• University of Florida (UF) — Gainesville
• … and 39 more centers

Spain · 13 centers

Center list to be confirmed — check the primary protocol.

France · 11 centers

• CHU de Grenoble — La Tronche
• Institut de cancérologie Strasbourg Europe (ICANS) — Strasbourg
• IUCT-Oncopole — Toulouse
• CHU Amiens Picardie - Hopital Sud — Amiens
• CHRU de Lille - Hopital Claude Huriez — Lille
• CHRU de Nancy - Hôpitaux de Brabois — Nancy
• CHU de Nantes - Hôtel-Dieu — Nantes
• Hopital Saint Louis — Paris
• … and 3 more centers

Italy · 10 centers

• ASST degli Spedali Civili di Brescia — Brescia
• … and 9 more centers

Germany · 6 centers

• Universitaetsklinikum Carl Gustav Carus Dresden — Dresden
• Universitaetsklinikum Jena — Jena
• Universitaetsklinikum Leipzig — Leipzig
• Universitaetsmedizin der Johannes Gutenberg - Universitaet Mainz — Mainz
• Universitaetsklinikum Muenster — Münster
• Universitatsklinikum Regensburg — Regensburg

United Kingdom · 6 centers

Center list to be confirmed — check the primary protocol.

Canada · 4 centers

• Vancouver Coastal Health Authority — Vancouver
• Princess Margaret Hospital — Toronto
• McGill University Health Center - Research Institute — Montreal
• CHU Sainte-Justine — Montreal

Israel · 4 centers

• Rambam Health Care Campus — Haifa
• Hadassah Medical Center Ein Karem — Jerusalem
• Chaim Sheba Medical Center — Ramat Gan
• Tel Aviv Sourasky Medical Center — Tel Aviv

South Korea · 4 centers

Center list to be confirmed — check the primary protocol.

Greece · 3 centers

• General Hospital of Thessaloniki G. Papanikolaou - Hematology Department, BMT Unit — Eksochi
• University Hospital of West Attica - Attikon - Hematology Division — Athens
• University General Hospital of Patras — Pátrai

Singapore · 3 centers

Center list to be confirmed — check the primary protocol.

Taiwan · 3 centers

Center list to be confirmed — check the primary protocol.

Australia · 2 centers

• The Royal Children's Hospital — Parkville
• Westmead Hospital — Westmead

Belgium · 2 centers

• Universitaire Ziekenhuizen Leuven — Leuven
• AZ Delta — Roeselare

Portugal · 2 centers

Center list to be confirmed — check the primary protocol.

Poland · 1 center

Center list to be confirmed — check the primary protocol.

Publications

• Yang YO, Sokolov V, Volkova A, Liu X, Leon C, Kosinsky Y, Barker B, Zhang X, Ordentlich P, Sheng J, Chen X. Semimechanistic Population PK/PD Modeling of Axatilimab in Healthy Participants and Patients With Solid Tumors or Chronic Graft-Versus-Host Disease. Clin Pharmacol Ther. 2025 Mar;117(3):704-715. doi: 10.1002/cpt.3503. Epub 2024 Dec 20. PMID 39704205
• Wolff D, Cutler C, Lee SJ, Pusic I, Bittencourt H, White J, Hamadani M, Arai S, Salhotra A, Perez-Simon JA, Alousi A, Choe H, Kwon M, Bermudez A, Kim I, Socie G, Chhabra S, Radojcic V, O'Toole T, Tian C, Ordentlich P, DeFilipp Z, Kitko CL; AGAVE-201 Investigators. Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease. N Engl J Med. 2024 Sep 19;391(11):1002-1014. doi: 10.1056/NEJM PMID 39292927

Identifiers

NCT: NCT04710576 · SNDX-6352-0504 · 2024-512978-99-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗