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

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

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).

Study Overview

• Status: Completed
• Conditions: Graft-versus-host Disease (GVHD)
• Intervention / Treatment: Drug: Itacitinib; Drug: Prednisone; Drug: Methylprednisolone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 439
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Darlinghurst, Australia, NSW 2010
    • St Vincents Hospital Sydney Limited
• Austria
  • Linz, Austria, 4020
    • Ordensklinikum Linz Gmbh Elisabethinen
• Belgium
  • Antwerpen, Belgium, 2060
    • ZNA Stuivenberg
  • Brugge, Belgium, 8000
    • General Hospital Sint-Jan Brugge-Oostend
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Brussels, Belgium, 1000
    • Institut Jules Bordet
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent (UZG)
  • Hasselt, Belgium, 3500
    • Jessa Ziekenhuis
  • Liege 1, Belgium, 4000
    • Hopital universitaire du Sart Tilman de Liege
  • Roeselare, Belgium, 8800
    • AZ Delta
• Czechia
  • Praha 2, Czechia, 128 20
    • UHKT Prague - Institute of Hematology and Blood Transfusion
• Finland
  • Helsinki, Finland, 00290
    • Helsinki University Central Hospital
• France
  • Amiens, France, 80054
    • CHU Amiens Picardie - Hopital Sud
  • LILLE Cedex, France, 59037
    • CHRU de Lille-Hopital Claude Huriez
  • Nantes, France, 44000
    • Hotel Dieu Hospital - Hematologie
  • Paris, France, 75010
    • Hopital Saint Louis
  • Pessac, France, 33604
    • Hopital Haut Leveque - CHU Bordeaux - Maladies du sang
  • Strasbourg cedex, France, 67098
    • Hopital de Hautepierre
  • Toulouse Cedex 9, France, 31059
    • Institut Claudius Regaud-Universitaire du Cancer Toulouse Oncopol
  • Vandoeuvre les Nancy, France, 54500
    • Chu de Nancy
• Germany
  • Dresden, Germany, 1307
    • University Clinic Carl Gustav Carus, Technical University Dresden
  • Freiburg, Germany, 79106
    • Universitätsklinikum Freiburg - Klinik für Innere Medizin I
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg - Eppendorf
  • Köln, Germany, 50924
    • Universitaet zu Koln - Universitaetsklinikum Koeln (Uniklinik Koeln)
  • Leipzig, Germany, 4103
    • Universitaetsklinikum Leipzig
  • Mainz, Germany, 55131
    • Universitaetsmedizin der Johannes Gutenberg
  • Marburg, Germany, 35043
    • UKGM Marburg Innere Medizin: Haematologie Onkolog
• Greece
  • Chortiátis, Greece, 57010
    • General Hospital of Thessaloniki G. Papanikolaou - Hematology Department
• Israel
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus
  • Jerusalem, Israel, 9112001
    • Hadassah Hebrew University Medical Center Ein Karem
  • Ramat Gan, Israel, 5262160
    • Chaim Sheba Medical Center
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center
• Italy
  • Bergamo, Italy, 24127
    • Azienda Socio Sanitaria Territoriale Papa Giovanni xxiii
  • Cagliari, Italy, 09126
    • C.T.M.O. Ospedale Roberto Binaghi ATS Cagliari
  • Catania, Italy, 95124
    • Azienda Ospedaliero Universitaria (AOU) Policlinico - Vittorio Emanuele - Presidio Ospedaliero Ferrarotto Alessi
  • Firenze, Italy, 50134
    • Azienda Ospedaliero Universitaria Careggi
  • Milan, Italy, 20122
    • Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico di Milano
  • Milan, Italy, 20132
    • IRCCS Ospedale San Raffaele
  • Milano, Italy, 20162
    • Asst Grande Ospedale Metropolitano Niguarda
  • Monza, Italy, 20900
    • Clinica Ematologica CTA, Ospedale "San Gerardo" di Monza
  • Palermo, Italy, 90146
    • Casa di Cura La Maddalena
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinco San Matteo
  • Pescara, Italy, 65124
    • Presidio Ospedaliero Pescara
  • Reggio Calabria, Italy, 89124
    • Azienda Ospedaliera Bianchi-Melacrino-Morelli Ospedali Riuniti
  • Reggio Emilia, Italy, 42123
    • Azienda Unita Sanitaria Locale di Reggio Emilia
  • Roma, Italy, 00161
    • University of Rome La Sapienza
  • Rozzano, Italy, 20089
    • Istituto Clinico Humanitas
  • Torino, Italy, 10126
    • A.O.U. Città della Salute e della Scienza di Torino
  • Udine, Italy, 33100
    • SOC Clinica Ematologica, Azienda Ospediero-Universitaria di Udine
• Korea, Republic of
  • Seoul, Korea, Republic of, 3080
    • Seoul National University Hospital
• New Zealand
  • Auckland, New Zealand, 1023
    • Auckland District Health Board
• Poland
  • Gliwice, Poland, 44-101
    • Centrum Onkologii- Instytut w Gliwicach
  • Warsaw, Poland, 02-776
    • Klinika Transplantacji Komorek Krwiotworczych - Instytut Hematologii i Transfuzjologii
• Portugal
  • Lisboa, Portugal, 1099-023
    • Instituto Portugues de Oncologia de Lisboa Francisco Gentil EPE (IPO-Lisboa)
  • Lisboa, Portugal, 1649-035
    • Centro Hospitalar Lisboa Norte - Hospital de Santa Maria
  • Porto, Portugal, 4200-072
    • Instituto Portugues de Oncologia do Porto Francisco Gentil, EPE
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial de Barcelona
  • Barcelona, Spain, 08025
    • Hospital de la Santa Creu i Sant Pau - Servei de Hematologia Clinica
  • Barcelona, Spain, 08907
    • Instituto Catalan de Oncologia - Hospital Duran i Reynals
  • Granada, Spain, 18014
    • Complejo Hospitalario Universitario de Granada - Hospital Universitario Virgen de las Nieves
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon Y Cajal
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain, 28222
    • Hospital Universitario Puerta de Hierro Majadahonda
  • Salamanca, Spain, 37007
    • Hospital Universitario de Salamanca
  • San Sebastián, Spain, 20014
    • Hospital Universitario de Donostia
  • Santander, Spain, 39008
    • Hospital Universitario Marqués de Valdecilla
  • Santiago de Compostela, Spain, 15706
    • Hospital Clínico de Santiago de Compostela
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen Del Rocio
  • Valencia, Spain, 46026
    • Hospital Universitari I Politecnic La Fe
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
• Switzerland
  • Basel, Switzerland, 4031
    • Universtity Hospital Basel - Haematology
  • Geneve, Switzerland, 1211
    • Hôpitaux Universitaires de Genève
  • Zuerich, Switzerland, CH-8091
    • Universitaetsspital Zuerich - Klinik fuer Haematology
• Taiwan
  • Taichung, Taiwan, 40447 ROC
    • China Medical University Hospital
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke's Hospital
  • Cardiff, United Kingdom, CF14 4XW
    • University Hospital of Wales
  • London, United Kingdom, W12 0HS
    • Hammersmith Hospital
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham University Hospitals
• United States
  • California
    • La Jolla, California, United States, 92093-0698
      • University of California, San Diego (UCSD) - Moores Cancer Center
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Los Angeles, California, United States, 90095-1678
      • University of California, Los Angeles (UCLA) - Medical Center
    • Stanford, California, United States, 94305
      • Stanford Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado - Aurora Cancer Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida (UF) - Division of Hematology & Oncology
    • Miami, Florida, United States, 33136
      • University of Miami - Sylvester Cancer Center
    • Orlando, Florida, United States, 32804
      • Florida Hospital Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Park Ridge, Illinois, United States, 60028
      • Advocate Lutheran General Hospital - Oncology Specialists SC
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University (IU) Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46237
      • Indiana Blood and Marrow Transplant
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States, 68198-7680
      • University of Nebraska Medical Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack UMC
    • New Brunswick, New Jersey, United States, 08903-2681
      • Rutgers Cancer Institute of New Jersey
  • New York
    • Lake Success, New York, United States, 11042
      • Northwell Health
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Medical Center - Wake Forest University School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45236
      • Oncology Hematology in Cincinnati
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43210
      • The Ohio State University (OSU)
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma - Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health & Science University (OHSU)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Medical Center (UPMC) - Hillman Cancer Center
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Greenville Health System
  • Tennessee
    • Memphis, Tennessee, United States, 38104
      • Methodist Healthcare Foundation
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute, LLC (SCRI)
  • Texas
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Itacitinib; Itacitinib plus corticosteroids	Drug: Itacitinib; Itacitinib at the protocol-defined dose administered orally once daily (QD) plus corticosteroids.; Other Names: INCB039110; Drug: 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.; Other Names: Deltasone; Rayos; Prednicot; predniSONE Intensol; Sterapred; Sterapred DS; Drug: Methylprednisolone; Methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose appropriate for the severity of disease as background treatment.; Other Names: Medrol; Solu-Medrol; Medrol Dosepak
Placebo Comparator: Placebo; Matching placebo plus corticosteroids	Drug: 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.; Other Names: Deltasone; Rayos; Prednicot; predniSONE Intensol; Sterapred; Sterapred DS; Drug: Methylprednisolone; Methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose appropriate for the severity of disease as background treatment.; Other Names: Medrol; Solu-Medrol; Medrol Dosepak; Drug: Placebo; Matching placebo tablets administered orally once daily (QD) plus corticosteroids.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nonrelapse Mortality	Defined as the percentage of participants who died due to causes other than malignancy relapse.	Month 6,9,12 and 24
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
Cmax of Itacitinib When Administered in Combination With Corticosteroids	Defined as maximum observed plasma concentration.	Protocol-defined timepoints up to Day 28
Cmin of Itacitinib When Administered in Combination With Corticosteroids	Defined as minimum observed plasma concentration.	Protocol-defined timepoints up to Day 28
Tmax of Itacitinib When Administered in Combination With Corticosteroids	Defined as time to maximum plasma concentration.	Protocol-defined timepoints up to Day 28
AUC of Itacitinib When Administered in Combination With Corticosteroids	Defined as area under the concentration-time curve.	Protocol-defined timepoints up to Day 28
CL/F of Itacitinib When Administered in Combination With Corticosteroids	Defined as oral dose clearance.	Protocol-defined timepoints up to Day 28
Time to Response	Defined as the interval from treatment initiation to first response	End of Study, total particpation expected to average 24 months
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
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
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
Overall Survival (OS)	Defined as the interval from study enrollment to death due to any cause.	End of Study up to approximately 24 months
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
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
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
Proportion of Subjects Who Discontinue Immunosuppressive Medications	Summary statistics of subjects discontinuing immunosuppressive medications will be calculated	Days 56 and 100
Incidence Rate of aGVHD Flares		up to day 100
Incidence Rate of cGVHD		Days 180 and 365
Objective Response Rate		Days 14, 56 and 100

Collaborators and Investigators

• Sponsor: Incyte Corporation

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2017
• Primary Completion (Actual): May 2, 2019
• Study Completion (Actual): July 13, 2020

Study Registration Dates

• First Submitted: May 2, 2017
• First Submitted That Met QC Criteria: May 2, 2017
• First Posted (Actual): May 4, 2017

Study Record Updates

• Last Update Posted (Actual): August 11, 2021
• Last Update Submitted That Met QC Criteria: July 13, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: corticosteroids; Acute graft-versus-host disease; Janus kinase (JAK) inhibitor; itacitinib; allogeneic hematopoietic stem cell transplant (allo-HSCT)
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Prednisone
• Other Study ID Numbers: INCB 39110-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No