GRAVITAS-301: A Study of Itacitinib or Placebo in Combination With Corticosteroids for Treatment of Acute Graft-Versus-Host Disease

Graft-versus-host Disease (GVHD) Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03139604
• Other study ID #: INCB 39110-301
• Status: Completed
• Phase: Phase 3
• Start date: July 19, 2017
• Est. completion date: July 13, 2020

Study information

• Verified date: July 2021
• Source: Incyte Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 439
• Est. completion date: July 13, 2020
• Est. primary completion date: May 2, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Graft vs Host Disease
• Graft-versus-host Disease (GVHD)

Intervention

Drug:
• Itacitinib
Itacitinib at the protocol-defined dose administered orally once daily (QD) plus corticosteroids.
• Placebo
Matching placebo tablets administered orally once daily (QD) plus corticosteroids.
• Prednisone
Oral prednisone may be used to begin standard corticosteroid background treatment at the investigator's discretion, at a dose equivalent to methylprednisolone 2 mg/kg per day.
• Methylprednisolone
Methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose appropriate for the severity of disease as background treatment.

Locations

Country	Name	City	State
Australia	St Vincents Hospital Sydney Limited	Darlinghurst
Austria	Ordensklinikum Linz GmbH Elisabethinen	Linz
Belgium	ZNA Stuivenberg	Antwerpen
Belgium	General Hospital Sint-Jan Brugge-Oostend	Brugge
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	Institut Jules Bordet	Brussels
Belgium	Universitair Ziekenhuis Gent (UZG)	Gent
Belgium	Jessa Ziekenhuis	Hasselt
Belgium	Hopital universitaire du Sart Tilman de Liege	Liege 1
Belgium	AZ Delta	Roeselare
Czechia	UHKT Prague - Institute of Hematology and Blood Transfusion	Praha 2
Finland	Helsinki University Central Hospital	Helsinki
France	CHU Amiens Picardie - Hopital Sud	Amiens
France	CHRU de Lille-Hopital Claude Huriez	LILLE Cedex
France	Hotel Dieu Hospital - Hematologie	Nantes
France	Hopital Saint Louis	Paris
France	Hopital Haut Leveque - CHU Bordeaux - Maladies du sang	Pessac
France	Hopital de Hautepierre	Strasbourg cedex
France	Institut Claudius Regaud-Universitaire du Cancer Toulouse Oncopol	Toulouse Cedex 9
France	CHU de Nancy	Vandoeuvre les Nancy
Germany	University Clinic Carl Gustav Carus, Technical University Dresden	Dresden
Germany	Universitatsklinikum Freiburg - Klinik fur Innere Medizin I	Freiburg
Germany	Universitatsklinikum Hamburg - Eppendorf	Hamburg
Germany	Universitaet zu Koln - Universitaetsklinikum Koeln (Uniklinik Koeln)	Köln
Germany	Universitaetsklinikum Leipzig	Leipzig
Germany	Universitaetsmedizin der Johannes Gutenberg	Mainz
Germany	UKGM Marburg Innere Medizin: Haematologie Onkolog	Marburg
Greece	General Hospital of Thessaloniki G. Papanikolaou - Hematology Department	Chortiátis
Israel	Rambam Health Care Campus	Haifa
Israel	Hadassah Hebrew University Medical Center Ein Karem	Jerusalem
Israel	Chaim Sheba Medical Center	Ramat Gan
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII	Bergamo
Italy	C.T.M.O. Ospedale Roberto Binaghi ATS Cagliari	Cagliari
Italy	Azienda Ospedaliero Universitaria (AOU) Policlinico - Vittorio Emanuele - Presidio Ospedaliero Ferrarotto Alessi	Catania
Italy	Azienda Ospedaliero Universitaria Careggi	Firenze
Italy	Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico di Milano	Milan
Italy	IRCCS Ospedale San Raffaele	Milan
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano
Italy	Clinica Ematologica CTA, Ospedale "San Gerardo" di Monza	Monza
Italy	Casa di Cura La Maddalena	Palermo
Italy	Fondazione IRCCS Policlinco San Matteo	Pavia
Italy	Presidio Ospedaliero Pescara	Pescara
Italy	Azienda Ospedaliera Bianchi-Melacrino-Morelli Ospedali Riuniti	Reggio Calabria
Italy	Azienda Unità Sanitaria Locale di Reggio Emilia	Reggio Emilia
Italy	University of Rome La Sapienza	Roma
Italy	Istituto Clinico Humanitas	Rozzano
Italy	A.O.U. Città della Salute e della Scienza di Torino	Torino
Italy	SOC Clinica Ematologica, Azienda Ospediero-Universitaria di Udine	Udine
Korea, Republic of	Seoul National University Hospital	Seoul
New Zealand	Auckland District Health Board	Auckland
Poland	Centrum Onkologii- Instytut w Gliwicach	Gliwice
Poland	Klinika Transplantacji Komorek Krwiotworczych - Instytut Hematologii i Transfuzjologii	Warsaw
Portugal	Centro Hospitalar Lisboa Norte - Hospital de Santa Maria	Lisboa
Portugal	Instituto Portugues de Oncologia de Lisboa Francisco Gentil EPE (IPO-Lisboa)	Lisboa
Portugal	Instituto Portugues de Oncologia do Porto Francisco Gentil, EPE	Porto
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau - Servei de Hematologia Clinica	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Instituto Catalan de Oncologia - Hospital Duran i Reynals	Barcelona
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 Puerta de Hierro Majadahonda	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario de Donostia	San Sebastián
Spain	Hospital Universitario Marques de Valdecilla	Santander
Spain	Hospital Clinico de Santiago de Compostela	Santiago de Compostela
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Switzerland	Universtity Hospital Basel - Haematology	Basel
Switzerland	Hopitaux Universitaires de Geneve	Geneve
Switzerland	Universitaetsspital Zuerich - Klinik fuer Haematology	Zuerich
Taiwan	China Medical University Hospital	Taichung
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	Hammersmith Hospital	London
United Kingdom	Nottingham University Hospitals	Nottingham
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Colorado - Aurora Cancer Center	Aurora	Colorado
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	University of Virginia Medical Center	Charlottesville	Virginia
United States	University of Chicago	Chicago	Illinois
United States	University of Illinois at Chicago	Chicago	Illinois
United States	Oncology Hematology in Cincinnati	Cincinnati	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	The Ohio State University (OSU)	Columbus	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	University of Florida (UF) - Division of Hematology & Oncology	Gainesville	Florida
United States	Spectrum Health	Grand Rapids	Michigan
United States	Greenville Health System	Greenville	South Carolina
United States	John Theurer Cancer Center At Hackensack UMC	Hackensack	New Jersey
United States	Indiana Blood and Marrow Transplant	Indianapolis	Indiana
United States	Indiana University (IU) Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	University of California, San Diego (UCSD) - Moores Cancer Center	La Jolla	California
United States	Northwell Health	Lake Success	New York
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of California, Los Angeles (UCLA) - Medical Center	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	Methodist Healthcare Foundation	Memphis	Tennessee
United States	University of Miami - Sylvester Cancer Center	Miami	Florida
United States	Sarah Cannon Research Institute, LLC (SCRI)	Nashville	Tennessee
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	Columbia University	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	University of Oklahoma - Health Sciences Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Florida Hospital Cancer Institute	Orlando	Florida
United States	Advocate Lutheran General Hospital - Oncology Specialists SC	Park Ridge	Illinois
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center (UPMC) - Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University (OHSU)	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Texas Transplant Institute	San Antonio	Texas
United States	Stanford Cancer Center	Stanford	California
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	University of Kansas Cancer Center	Westwood	Kansas
United States	Wake Forest Baptist Medical Center - Wake Forest University School of Medicine	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Incyte Corporation

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Czechia,  Finland,  France,  Germany,  Greece,  Israel,  Italy,  Korea, Republic of,  New Zealand,  Poland,  Portugal,  Spain,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate Based on Center for International Blood and Marrow Transplant Research (CIBMTR) Response Index	Defined as the percentage of participants demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR).	Day 28
Secondary	Nonrelapse Mortality	Defined as the percentage of participants who died due to causes other than malignancy relapse.	Month 6,9,12 and 24
Secondary	Duration of Response	Defined as the interval from first response until GVHD progression or death.	Baseline through 30-35 days after end of treatment, total particpation expected to average 24 months
Secondary	Cmax of Itacitinib When Administered in Combination With Corticosteroids	Defined as maximum observed plasma concentration.	Protocol-defined timepoints up to Day 28
Secondary	Cmin of Itacitinib When Administered in Combination With Corticosteroids	Defined as minimum observed plasma concentration.	Protocol-defined timepoints up to Day 28
Secondary	Tmax of Itacitinib When Administered in Combination With Corticosteroids	Defined as time to maximum plasma concentration.	Protocol-defined timepoints up to Day 28
Secondary	AUC of Itacitinib When Administered in Combination With Corticosteroids	Defined as area under the concentration-time curve.	Protocol-defined timepoints up to Day 28
Secondary	CL/F of Itacitinib When Administered in Combination With Corticosteroids	Defined as oral dose clearance.	Protocol-defined timepoints up to Day 28
Secondary	Time to Response	Defined as the interval from treatment initiation to first response	End of Study, total particpation expected to average 24 months
Secondary	Relapse Rate of Malignant and Nonmalignant Hematologic Disease	Defined as the proportion of subjects whose underlying hematologic disease relapses	Randomization through end of Study, study duration expected to average 24 months
Secondary	Malignancy Relapse-related Mortality Rate	Defined as the proportion of subjects whose malignancy relapses and has a fatal outcome.	Randomization through end of Study, study duration expected to average 24 months
Secondary	Failure-free Survival	Defined as the proportion of subjects who are still alive, have not relapsed, have not required additional therapy for aGVHD, and have not demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD)	6 months from randomization
Secondary	Overall Survival (OS)	Defined as the interval from study enrollment to death due to any cause.	End of Study up to approximately 24 months
Secondary	Number of Treatment-emergent Adverse Events With INCB39110	Adverse events reported for the first time or worsening of a pre-existing event after the first dose of study treatment	30-35 days after end of treatment, approximately 24 months
Secondary	Incidence Rate of Secondary Graft Failure	Defined as > 95% recipient cells any time after engraftment with no signs of relapse, OR retransplantation because of secondary neutropenia (< 0.5 × 109/L) and/or thrombocytopenia (< 20 × 109/L) within 2 months of transplantion	Randomization through end of Study, study duration expected to average 24 months
Secondary	Proportion of Subjects Who Discontinue Corticosteroids	Average and cumulative corticosteroid dose usage will be calculated and proportion of subjects discontinuing corticosteroids will be tabulated	Days 28, 56, 100, and 180
Secondary	Proportion of Subjects Who Discontinue Immunosuppressive Medications	Summary statistics of subjects discontinuing immunosuppressive medications will be calculated	Days 56 and 100
Secondary	Incidence Rate of aGVHD Flares		up to day 100
Secondary	Incidence Rate of cGVHD		Days 180 and 365
Secondary	Objective Response Rate		Days 14, 56 and 100