Clinical trial NCT04710576: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Chronic Graft-versus-host-disease
Keywords: cGVHD
AGAVE-201
GVHD
graft versus host disease
graft-versus-host-disease
Lead sponsor: Syndax Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2021-01-14
Enrollment: 241
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Eligibility criteria: Inclusion Criteria:

1. Participants must be 2 years of age or older, at the time of signing the informed consent.
2. 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.
3. 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.
4. 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.
5. Karnofsky Performance Scale of ≥60 (if aged 16 years or older); Lansky Performance Score of ≥60 (if aged \<16 years)
6. Adequate organ and bone marrow functions evaluated during the 14 days prior to randomization.
7. Creatinine clearance (CrCl) ≥30 milliliter/minute based on the Cockcroft-Gault formula in adult participants and Schwartz formula in pediatric participants.
8. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
9. 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.
10. Concomitant use of CNI or mammalian target of repamycin (mTOR) inhibitors (sirolimus or everolimus) is allowed but not required.
11. 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:

1. Has acute GVHD without manifestations of cGVHD.
2. Any evidence (histologic, cytogenetic, molecular, hematologic, or mixed) of relapse of the underlying cancer or post-transplant lymphoproliferative disease at the time of screening.
3. History of acute or chronic pancreatitis.
4. History of myositis.
5. 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.
6. Participants with acquired immune deficiency syndrome (AIDS).
7. 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 \[RNA\]).
8. 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).
9. Female participant who is pregnant or breastfeeding.
10. Previous exposure to CSF1-R targeted therapies.
11. Taking agents for treatment of cGVHD other than corticosteroids or either a CNI or mTOR inhibitor is prohibited.
12. 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.
13. Receiving another investigational treatment within 28 days of randomization.
14. 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).

Primary outcomes:
measure: 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)
timeFrame: First 6 cycles (up to Cycle 7 Day 1; each cycle = 4 weeks)
Secondary outcomes:
measure: ORR on Study as Defined by the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD
timeFrame: Up to 2 years
measure: Number of Participants With a Clinically Significant Improvement in Normalized Score on the Modified Lee Symptom Scale
timeFrame: Up to 2 years
measure: Duration of Response
timeFrame: Up to 2 years
measure: Sustained Response Rate
timeFrame: Up to 2 years
measure: Organ-specific Response Rate
timeFrame: Up to 2 years
measure: Joints and Fascia Response Rate Based on Refined NIH Response Algorithm for cGVHD
timeFrame: Up to 2 years
measure: Percent Reductions in Average Daily Doses (or Equivalent) of Corticosteroid
timeFrame: Up to 2 years
measure: Number of Participants Who Discontinue Corticosteroid Use
timeFrame: Up to 2 years
measure: Percent Reductions in Average Daily Doses (or Equivalent) of Calcineurin Inhibitors (CNI)
timeFrame: Up to 2 years
measure: Number of Participants Who Discontinue CNIs
timeFrame: Up to 2 years
measure: Change From Baseline in Circulating Monocyte Number and Phenotype (CD14/16)
timeFrame: Baseline, up to 2 years
measure: Number of Participants With Anti-Drug Antibody
timeFrame: Up to 2 years
measure: Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of Last Measurable Concentration (AUC0-t)
timeFrame: Approximately 12 months
measure: Number of Participants With Treatment-emergent Adverse Events
timeFrame: Up to 2 years
measure: Change From Baseline in Bone Turnover Markers
timeFrame: Baseline, up to 2 years
measure: Change From Baseline in Bone Density
timeFrame: Baseline, up to 2 years
measure: Change From Baseline in Colony Stimulating Factor 1 (CSF-1) and Interleukin 34 (IL-34) Levels
timeFrame: Baseline, up to 2 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham - Children's of Alabama
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: University of Southern California Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles (UCLA) - Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida (UF)
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Tampa
country: United States
facility: Moffitt
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Chicago
country: United States
facility: The University of Chicago Medical Center (UCMC)
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health Melvin and Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Franciscan Health Indianapolis
state: Indiana
city: New Orleans
country: United States
facility: Tulane University Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Lyndhurst
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma - Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Hillman Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Intermountain Healthcare
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Medical Center
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin - Carbone Cancer Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert Hospital and the Medical College of Wisconsin
state: Wisconsin
city: Parkville
country: Australia
facility: The Royal Children's Hospital
state: Victoria
city: Westmead
country: Australia
facility: Westmead Hospital
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven
city: Roeselare
country: Belgium
facility: AZ Delta
city: Vancouver
country: Canada
facility: Vancouver Coastal Health Authority
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: CHU Sainte-Justine
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Center - Research Institute
state: Quebec
city: La Tronche
country: France
facility: CHU de Grenoble
state: Auvergne-Rhône-Alpes
city: Strasbourg
country: France
facility: Institut de cancérologie Strasbourg Europe (ICANS)
state: Grand Est
city: Toulouse
country: France
facility: IUCT-Oncopole
state: Haure-Garrone
city: Amiens
country: France
facility: CHU Amiens Picardie - Hopital Sud
state: Hauts-de-France
city: Lille
country: France
facility: CHRU de Lille - Hopital Claude Huriez
state: Hauts-de-France
city: Nancy
country: France
facility: CHRU de Nancy - Hôpitaux de Brabois
city: Nantes
country: France
facility: CHU de Nantes - Hôtel-Dieu
city: Paris
country: France
facility: Hopital Saint Louis
city: Paris
country: France
facility: Hopital Pitie Salpetriere
city: Pessac
country: France
facility: CHU Bordeaux - Hopital Haut-Leveque - Centre François Magendie
city: Pierre-Bénite
country: France
facility: HCL Centre Hospitalier Lyon Sud
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus Dresden
city: Jena
country: Germany
facility: Universitaetsklinikum Jena
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg - Universitaet Mainz
city: Münster
country: Germany
facility: Universitaetsklinikum Muenster
city: Regensburg
country: Germany
facility: Universitatsklinikum Regensburg
city: Exochí
country: Greece
facility: General Hospital of Thessaloniki G. Papanikolaou - Hematology Department, BMT Unit
state: Thessaloniki
city: Athens
country: Greece
facility: University Hospital of West Attica - Attikon - Hematology Division
city: Patras
country: Greece
facility: University General Hospital of Patras
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Hadassah Medical Center Ein Karem
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Brescia
country: Italy
facility: ASST degli Spedali Civili di Brescia
city: Milano
country: Italy
facility: Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico di Milano
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Monza
country: Italy
facility: ASST di Monza-Ospedale San Gerardo
city: Monza
country: Italy
facility: Fondazione Monza e Brianza per il Bambino e la sua Mamma
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Roma
country: Italy
facility: Fondazione Policlinica Universitario A. Gemelli IRCCS - Universita Cattolica del Sacro Cuore
city: Torino
country: Italy
facility: AOU Citta della Salute e della Scienza di Torino - Ospedale Regina Margherita
city: Torino
country: Italy
facility: Citta della Salute e della Scienza di Torino - Ospedale le Molinette
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Gliwice
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy, Oddzial w Gliwicach - Klinika Transplantacji Szpiku i Onkohematologii
city: Lisboa
country: Portugal
facility: Instituto Portugues de Oncologia de Lisboa Francisco Gentil, E.P.E. (IPO-Lisboa)
city: Porto
country: Portugal
facility: Instituto Portugues de Oncologia do Porto Francisco Gentil, EPE
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: KK Women's and Children hospital
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
state: Seville
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Donostia
country: Spain
facility: Hospital Universitario Donostia
city: Granada
country: Spain
facility: Complejo Hospitalario Universitario de Granada - Hospital Universitario Virgen de las Nieves
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: Salamanca
country: Spain
facility: Hospital Clinico Universitario de Salamanca
city: Santander
country: Spain
facility: Hospital Universitario Marquis de Valdecilla
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Marsden Foundation Trust
Study officials:
affiliation: Syndax Pharmaceuticals
name: Vedran Radojcic, M.D.
role: STUDY_DIRECTOR
References: