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

Chronic Graft-versus-host-disease Clinical Trial

— AGAVE-201  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04710576
• Other study ID #: SNDX-6352-0504
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: March 4, 2021
• Est. completion date: December 2024

Study information

• Verified date: August 2023
• Source: Syndax Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 241
• Est. completion date: December 2024
• Est. primary completion date: June 29, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Bronchiolitis Obliterans Syndrome
• Chronic Graft-versus-host-disease
• Graft vs Host Disease

Intervention

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.

Locations

Country	Name	City	State
Australia	The Royal Children's Hospital	Parkville	Victoria
Australia	Westmead Hospital	Westmead
Belgium	Universitaire Ziekenhuizen Leuven	Leuven
Belgium	AZ Delta	Roeselare
Canada	CHU Sainte-Justine	Montreal	Quebec
Canada	McGill University Health Center - Research Institute	Montréal	Quebec
Canada	Princess Margaret Hospital	Toronto	Ontario
Canada	Vancouver Coastal Health Authority	Vancouver	British Columbia
France	CHU Amiens Picardie - Hopital Sud	Amiens	Hauts-de-France
France	CHU de Grenoble	La Tronche	Auvergne-Rhône-Alpes
France	CHRU de Lille - Hopital Claude Huriez	Lille	Hauts-de-France
France	CHRU de Nancy - Hôpitaux de Brabois	Nancy
France	CHU de Nantes - Hôtel-Dieu	Nantes
France	Hopital Pitie Salpetriere	Paris
France	Hopital Saint Louis	Paris
France	CHU Bordeaux - Hopital Haut-Leveque - Centre François Magendie	Pessac
France	HCL Centre Hospitalier Lyon Sud	Pierre-Bénite
France	Institut de cancérologie Strasbourg Europe (ICANS)	Strasbourg	Grand Est
France	IUCT-Oncopole	Toulouse	Haure-Garrone
Germany	Universitaetsklinikum Carl Gustav Carus Dresden	Dresden
Germany	Universitaetsklinikum Jena	Jena
Germany	Universitaetsklinikum Leipzig	Leipzig
Germany	Universitaetsmedizin der Johannes Gutenberg - Universitaet Mainz	Mainz
Germany	Universitaetsklinikum Muenster	Münster
Germany	Universitatsklinikum Regensburg	Regensburg
Greece	University Hospital of West Attica - Attikon - Hematology Division	Athens
Greece	General Hospital of Thessaloniki G. Papanikolaou - Hematology Department, BMT Unit	Exochí	Thessaloniki
Greece	University General Hospital of Patras	Patras
Israel	Rambam Health Care Campus	Haifa
Israel	Hadassah Medical Center Ein Karem	Jerusalem
Israel	Chaim Sheba Medical Center	Ramat Gan
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	ASST degli Spedali Civili di Brescia	Brescia
Italy	Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico di Milano	Milano
Italy	IRCCS Ospedale San Raffaele	Milano
Italy	ASST di Monza-Ospedale San Gerardo	Monza
Italy	Fondazione Monza e Brianza per il Bambino e la sua Mamma	Monza
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Fondazione Policlinica Universitario A. Gemelli IRCCS - Universita Cattolica del Sacro Cuore	Roma
Italy	AOU Citta della Salute e della Scienza di Torino - Ospedale Regina Margherita	Torino
Italy	Citta della Salute e della Scienza di Torino - Ospedale le Molinette	Torino
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy, Oddzial w Gliwicach - Klinika Transplantacji Szpiku i Onkohematologii	Gliwice
Portugal	Instituto Portugues de Oncologia de Lisboa Francisco Gentil, E.P.E. (IPO-Lisboa)	Lisboa
Portugal	Instituto Portugues de Oncologia do Porto Francisco Gentil, EPE	Porto
Singapore	KK Women's and Children hospital	Singapore
Singapore	National University Hospital	Singapore
Singapore	Singapore General Hospital	Singapore
Spain	Hospital Clinic Barcelona	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitario Donostia	Donostia
Spain	Complejo Hospitalario Universitario de Granada - Hospital Universitario Virgen de las Nieves	Granada
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario Puerta de Hierro	Majadahonda
Spain	Hospital Clinico Universitario de Salamanca	Salamanca
Spain	Hospital Universitario Marquis de Valdecilla	Santander
Spain	Hospital Universitario Virgen del Rocio	Sevilla	Seville
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	China Medical University Hospital	Taichung
Taiwan	National Taiwan University Hospital	Taipei
United Kingdom	Bristol Royal Hospital for Children	Bristol
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	Queen Elizabeth University Hospital	Glasgow
United Kingdom	Hammersmith Hospital	London
United Kingdom	King's College Hospital NHS Foundation Trust	London
United Kingdom	Royal Marsden Foundation Trust	London
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Northside Hospital	Atlanta	Georgia
United States	Johns Hopkins Kimmel Cancer Center	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	University of Alabama at Birmingham - Children's of Alabama	Birmingham	Alabama
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Virginia Medical Center	Charlottesville	Virginia
United States	The University of Chicago Medical Center (UCMC)	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	The Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Henry Ford Hospital	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	University of Florida (UF)	Gainesville	Florida
United States	MD Anderson Cancer Center	Houston	Texas
United States	Franciscan Health Indianapolis	Indianapolis	Indiana
United States	Indiana University Health Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	University of California, Los Angeles (UCLA) - Medical Center	Los Angeles	California
United States	University of Southern California Norris Comprehensive Cancer Center	Los Angeles	California
United States	The Cleveland Clinic Foundation	Lyndhurst	Ohio
United States	University of Wisconsin - Carbone Cancer Center	Madison	Wisconsin
United States	University of Miami	Miami	Florida
United States	Froedtert Hospital and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Tulane University Medical Center	New Orleans	Louisiana
United States	Weill Medical College of Cornell University	New York	New York
United States	University of Oklahoma - Health Sciences Center	Oklahoma City	Oklahoma
United States	AdventHealth Orlando	Orlando	Florida
United States	University of Pittsburgh Medical Center - Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Intermountain Healthcare	Salt Lake City	Utah
United States	University of Utah	Salt Lake City	Utah
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Stanford Cancer Center	Stanford	California
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Moffitt	Tampa	Florida
United States	Children's National Medical Center	Washington	District of Columbia
United States	Wake Forest	Winston-Salem	North Carolina
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Syndax Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Greece,  Israel,  Italy,  Korea, Republic of,  Poland,  Portugal,  Singapore,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate in the First 6 Cycles	The overall response rate will be assessed by the number of participants with objective response by Cycle 7 (28-day cycles), Day 1, with responses defined by the 2014 NIH consensus criteria.	Up to Day 169
Secondary	Number of Participants with a Clinically Significant Improvement in Normalized Score on the Modified Lee Symptom Scale		Approximately 30 months
Secondary	Duration of Response	Duration of response is defined as the time from initial partial response or complete response until documented progression of cGVHD, start of new therapy, or death for any reason.	Approximately 30 months
Secondary	Sustained Response Rate	Sustained response rate is defined as the number of participants with objective response lasting for at least 20 weeks (140 days) from the time of initial response. Responses by organ system will be assessed based on the 2014 NIH Consensus Development Project on Clinical Trials in cGVHD.	Approximately 30 months
Secondary	Organ-specific Response Rate	Organ-specific response is defined as the number of participants with objective response for the nine individual organs based on 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD (skin, eyes, mouth, esophagus, upper gastrointestinal [GI], lower GI, liver, lungs and joints and fascia).	Approximately 30 months
Secondary	Joints and Fascia Response Rate Based on Refined NIH Response Algorithm for cGVHD		Approximately 30 months
Secondary	Percent Reductions in Average Daily Doses (or Equivalent) of Corticosteroid		Approximately 30 months
Secondary	Number of Participants who Discontinue Corticosteroid Use		Approximately 30 months
Secondary	Percent Reductions in Average Daily Doses (or Equivalent) of Calcineurin Inhibitors (CNI)		Approximately 30 months
Secondary	Number of Participants who Discontinue CNIs		Approximately 30 months
Secondary	Change from Baseline in Circulating Monocyte Levels		Baseline, approximately 30 months
Secondary	Number of Participants with Anti-Drug Antibody		Approximately 30 months
Secondary	Area Under the Plasma Concentration-time Curve (AUC) from Time 0 to Time of Last Measurable Concentration (AUC0-t)		Approximately 12 months
Secondary	AUC from Time 0 to Infinity (AUC0-inf)		Approximately 12 months
Secondary	Observed Maximum Plasma Concentration (Cmax)		Approximately 12 months
Secondary	Time to Observed Maximum Plasma Concentration (Tmax)		Approximately 12 months
Secondary	Number of Participants with Treatment-emergent Adverse Events		Approximately 30 months