Clinical trial NCT03139604: GRAVITAS-301: A Study of Itacitinib or Placebo in Combination With Corticosteroids for Treatment of Acute Graft-Versus-Host Disease
Official title: GRAVITAS-301: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Itacitinib or Placebo in Combination With Corticosteroids for the Treatment of First-Line Acute Graft-Versus-Host Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Graft-versus-host Disease (GVHD)
Keywords: Acute graft-versus-host disease
Janus kinase (JAK) inhibitor
itacitinib
corticosteroids
allogeneic hematopoietic stem cell transplant (allo-HSCT)
Lead sponsor: Incyte Corporation
Sponsor class: INDUSTRY
First posted: 2017-05-04
Enrollment: 439
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate itacitinib or placebo in combination with corticosteroids as first-line treatment of participants with Grade II to IV acute graft-versus-host disease (aGVHD).


Eligibility criteria: Inclusion Criteria:

* Has undergone 1 allo-HSCT from any donor (related or unrelated with any degree of HLA matching) and any donor source (bone marrow, peripheral blood stem cells, or cord blood) for a hematologic malignancy or disorder. Recipients of myeloablative and reduced-intensity conditioning regimens are eligible.
* Clinically suspected Grade II to IV aGVHD as per MAGIC criteria, occurring after allo-HSCT and any GVHD prophylaxis regimen.
* Evidence of myeloid engraftment. Use of growth factor supplementation is allowed.
* Serum creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 40 mL/min measured or calculated by Cockroft Gault equation.
* Willing to avoid pregnancy or fathering children.
* Able to give written informed consent and comply with all study visits and procedures.
* Able to swallow and retain oral medication.

Exclusion Criteria:

* Has received more than 1 allo-HSCT.
* Has received more than 2 days of systemic corticosteroids for aGVHD.
* Presence of GVHD overlap syndrome.
* Presence of an active uncontrolled infection.
* Known human immunodeficiency virus infection.
* Active hepatitis B virus (HBV) or hepatitis C virus infection that requires treatment or at risk for HBV reactivation.
* Participants with evidence of relapsed primary disease, or participants who have been treated for relapse after the allo-HSCT was performed.
* Any corticosteroid therapy for indications other than GVHD at doses \> 1 mg/kg per day methylprednisolone (or prednisone equivalent) within 7 days of randomization.
* Severe organ dysfunction unrelated to underlying GVHD, including:

  * Cholestatic disorders or unresolved veno-occlusive disease of the liver.
  * Clinically significant or uncontrolled cardiac disease.
  * Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen.
* Currently breast feeding.
* Received JAK inhibitor therapy after allo-HSCT for any indication. Treatment with a JAK inhibitor before allo-HSCT is permitted.
* Treatment with any other investigational agent, device, or procedure within 21 days (or 5 half-lives, whichever is greater) of enrollment.
* Any medical complications or conditions that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
* Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.

Primary outcomes:
measure: Overall Response Rate Based on Center for International Blood and Marrow Transplant Research (CIBMTR) Response Index
timeFrame: Day 28
Secondary outcomes:
measure: Nonrelapse Mortality
timeFrame: Month 6,9,12 and 24
measure: Duration of Response
timeFrame: Baseline through 30-35 days after end of treatment, total particpation expected to average 24 months
measure: Cmax of Itacitinib When Administered in Combination With Corticosteroids
timeFrame: Protocol-defined timepoints up to Day 28
measure: Cmin of Itacitinib When Administered in Combination With Corticosteroids
timeFrame: Protocol-defined timepoints up to Day 28
measure: Tmax of Itacitinib When Administered in Combination With Corticosteroids
timeFrame: Protocol-defined timepoints up to Day 28
measure: AUC of Itacitinib When Administered in Combination With Corticosteroids
timeFrame: Protocol-defined timepoints up to Day 28
measure: CL/F of Itacitinib When Administered in Combination With Corticosteroids
timeFrame: Protocol-defined timepoints up to Day 28
measure: Time to Response
timeFrame: End of Study, total particpation expected to average 24 months
measure: Relapse Rate of Malignant and Nonmalignant Hematologic Disease
timeFrame: Randomization through end of Study, study duration expected to average 24 months
measure: Malignancy Relapse-related Mortality Rate
timeFrame: Randomization through end of Study, study duration expected to average 24 months
measure: Failure-free Survival
timeFrame: 6 months from randomization
measure: Overall Survival (OS)
timeFrame: End of Study up to approximately 24 months
measure: Number of Treatment-emergent Adverse Events With INCB39110
timeFrame: 30-35 days after end of treatment, approximately 24 months
measure: Incidence Rate of Secondary Graft Failure
timeFrame: Randomization through end of Study, study duration expected to average 24 months
measure: Proportion of Subjects Who Discontinue Corticosteroids
timeFrame: Days 28, 56, 100, and 180
measure: Proportion of Subjects Who Discontinue Immunosuppressive Medications
timeFrame: Days 56 and 100
measure: Incidence Rate of aGVHD Flares
timeFrame: up to day 100
measure: Incidence Rate of cGVHD
timeFrame: Days 180 and 365
measure: Objective Response Rate
timeFrame: Days 14, 56 and 100
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, San Diego (UCSD) - Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California
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: Aurora
country: United States
facility: University of Colorado - Aurora Cancer Center
state: Colorado
city: Gainesville
country: United States
facility: University of Florida (UF) - Division of Hematology & Oncology
state: Florida
city: Miami
country: United States
facility: University of Miami - Sylvester Cancer Center
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Cancer Institute
state: Florida
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Park Ridge
country: United States
facility: Advocate Lutheran General Hospital - Oncology Specialists SC
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University (IU) Melvin and Bren Simon Cancer Center
state: Indiana
city: Indianapolis
country: United States
facility: Indiana Blood and Marrow Transplant
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: New Orleans
country: United States
facility: Tulane University Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Hackensack
country: United States
facility: John Theurer Cancer Center At Hackensack UMC
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Lake Success
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center - Wake Forest University School of Medicine
state: North Carolina
city: Cincinnati
country: United States
facility: Oncology Hematology in Cincinnati
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 (OSU)
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 (OHSU)
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center (UPMC) - Hillman Cancer Center
state: Pennsylvania
city: Greenville
country: United States
facility: Greenville Health System
state: South Carolina
city: Memphis
country: United States
facility: Methodist Healthcare Foundation
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Research Institute, LLC (SCRI)
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Medical Center
state: Virginia
city: Darlinghurst
country: Australia
facility: St Vincents Hospital Sydney Limited
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH Elisabethinen
city: Antwerpen
country: Belgium
facility: ZNA Stuivenberg
city: Brugge
country: Belgium
facility: General Hospital Sint-Jan Brugge-Oostend
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent (UZG)
city: Hasselt
country: Belgium
facility: Jessa Ziekenhuis
city: Liege 1
country: Belgium
facility: Hopital universitaire du Sart Tilman de Liege
city: Roeselare
country: Belgium
facility: AZ Delta
city: Praha 2
country: Czechia
facility: UHKT Prague - Institute of Hematology and Blood Transfusion
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Amiens
country: France
facility: CHU Amiens Picardie - Hopital Sud
city: LILLE Cedex
country: France
facility: CHRU de Lille-Hopital Claude Huriez
city: Nantes
country: France
facility: Hotel Dieu Hospital - Hematologie
city: Paris
country: France
facility: Hopital Saint Louis
city: Pessac
country: France
facility: Hopital Haut Leveque - CHU Bordeaux - Maladies du sang
city: Strasbourg cedex
country: France
facility: Hopital de Hautepierre
city: Toulouse Cedex 9
country: France
facility: Institut Claudius Regaud-Universitaire du Cancer Toulouse Oncopol
city: Vandoeuvre les Nancy
country: France
facility: CHU de Nancy
city: Dresden
country: Germany
facility: University Clinic Carl Gustav Carus, Technical University Dresden
city: Freiburg
country: Germany
facility: Universitatsklinikum Freiburg - Klinik fur Innere Medizin I
city: Hamburg
country: Germany
facility: Universitatsklinikum Hamburg - Eppendorf
city: Köln
country: Germany
facility: Universitaet zu Koln - Universitaetsklinikum Koeln (Uniklinik Koeln)
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg
city: Marburg
country: Germany
facility: UKGM Marburg Innere Medizin: Haematologie Onkolog
city: Chortiátis
country: Greece
facility: General Hospital of Thessaloniki G. Papanikolaou - Hematology Department
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Hadassah Hebrew University 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: Bergamo
country: Italy
facility: Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII
city: Cagliari
country: Italy
facility: C.T.M.O. Ospedale Roberto Binaghi ATS Cagliari
city: Catania
country: Italy
facility: Azienda Ospedaliero Universitaria (AOU) Policlinico - Vittorio Emanuele - Presidio Ospedaliero Ferrarotto Alessi
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Milan
country: Italy
facility: Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico di Milano
city: Milan
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Monza
country: Italy
facility: Clinica Ematologica CTA, Ospedale "San Gerardo" di Monza
city: Palermo
country: Italy
facility: Casa di Cura La Maddalena
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinco San Matteo
city: Pescara
country: Italy
facility: Presidio Ospedaliero Pescara
city: Reggio Calabria
country: Italy
facility: Azienda Ospedaliera Bianchi-Melacrino-Morelli Ospedali Riuniti
city: Reggio Emilia
country: Italy
facility: Azienda Unità Sanitaria Locale di Reggio Emilia
city: Roma
country: Italy
facility: University of Rome La Sapienza
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: Torino
country: Italy
facility: A.O.U. Città della Salute e della Scienza di Torino
city: Udine
country: Italy
facility: SOC Clinica Ematologica, Azienda Ospediero-Universitaria di Udine
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Auckland
country: New Zealand
facility: Auckland District Health Board
city: Gliwice
country: Poland
facility: Centrum Onkologii- Instytut w Gliwicach
city: Warsaw
country: Poland
facility: Klinika Transplantacji Komorek Krwiotworczych - Instytut Hematologii i Transfuzjologii
city: Lisboa
country: Portugal
facility: Instituto Portugues de Oncologia de Lisboa Francisco Gentil EPE (IPO-Lisboa)
city: Lisboa
country: Portugal
facility: Centro Hospitalar Lisboa Norte - Hospital de Santa Maria
city: Porto
country: Portugal
facility: Instituto Portugues de Oncologia do Porto Francisco Gentil, EPE
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau - Servei de Hematologia Clinica
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial de Barcelona
city: Barcelona
country: Spain
facility: Instituto Catalan de Oncologia - Hospital Duran i Reynals
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: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: San Sebastián
country: Spain
facility: Hospital Universitario de Donostia
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: Santiago de Compostela
country: Spain
facility: Hospital Clinico de Santiago de Compostela
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Basel
country: Switzerland
facility: Universtity Hospital Basel - Haematology
city: Geneve
country: Switzerland
facility: Hopitaux Universitaires de Geneve
city: Zuerich
country: Switzerland
facility: Universitaetsspital Zuerich - Klinik fuer Haematology
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals
Study officials:
affiliation: Incyte Corporation
name: Rodica Morariu-Zamfir, MD
role: STUDY_DIRECTOR
References:
citation: Pratta M, Paczesny S, Socie G, Barkey N, Liu H, Owens S, Arbushites MC, Schroeder MA, Howell MD. A biomarker signature to predict complete response to itacitinib and corticosteroids in acute graft-versus-host disease. Br J Haematol. 2022 Aug;198(4):729-739. doi: 10.1111/bjh.18300. Epub 2022 Jun 11.
citation: Zeiser R, Socie G, Schroeder MA, Abhyankar S, Vaz CP, Kwon M, Clausen J, Volodin L, Giebel S, Chacon MJ, Meyers G, Ghosh M, Deeren D, Sanz J, Morariu-Zamfir R, Arbushites M, Lakshminarayanan M, Barbour AM, Chen YB. Efficacy and safety of itacitinib versus placebo in combination with corticosteroids for initial treatment of acute graft-versus-host disease (GRAVITAS-301): a randomised, multicentre, double-blind, phase 3 trial. Lancet Haematol. 2022 Jan;9(1):e14-e25. doi: 10.1016/S2352-3026(21)00367-7.