Ibrutinib in Combination With Corticosteroids vs Placebo in Combination With Corticosteroids in Participants With New Onset Chronic Graft Versus Host Disease (cGVHD) (iNTEGRATE)

A Randomized, Double-Blind Phase 3 Study of Ibrutinib in Combination With Corticosteroids Versus Placebo in Combination With Corticosteroids in Subjects With New Onset Chronic Graft Versus Host Disease (cGVHD)

To evaluate the safety and efficacy of ibrutinib in combination with prednisone in subjects with newly diagnosed moderate to severe cGVHD.

Study Overview

• Status: Completed
• Conditions: Chronic Graft Versus Host Disease
• Intervention / Treatment: Drug: ibrutinib; Drug: Prednisone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 193
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • The Kinghorn Cancer Centre /ID# 1140-1165
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital /ID# 1140-0848
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital /ID# 1140-0190
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital/ID# 1140-1154
    • Parkville, Victoria, Australia, 3052
      • Royal Melbourne Hospital (RMH) /ID# 1140-0633
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Fiona Stanley Hospital /ID# 1140-0880
• Austria
  • Graz, Austria, 8036
    • Univ. Klinik for Innere Medizin, Klinische Abteilung for Hematologie, Graz /ID# 1140-0373
  • Linz, Austria, 4020
    • Krankenhaus der Elisabethinen Linz /ID# 1140-0849
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • University of British Columbia (UBC) - Vancouver General Hospital (VGH) /ID# 1140-1166
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital Regional Cancer Center /ID# 1140-0159
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre /ID# 1140-0043
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • CHU Sainte-Justine /ID# 1140-1143
• China
  • Beijing, China, 100853
    • Chinese PLA General Hospital /ID# 1140-1198
  • Guangzhou Shi, China, 510000
    • Nanfang Hospital /ID# 1140-1379
  • Jiangsu
    • Suzhou, Jiangsu, China, 215006
      • The First Affiliated Hospital of Soochow University /ID# 1140-1208
• Croatia
  • Zagreb, Croatia, 10000
    • UHC Zagreb /ID# 1140-1169
• France
  • Amiens, France, 80054
    • CHU Amiens Groupe hospitalier Sud /ID# 1140-1205
  • Grenoble, France, 38043
    • CHU de GRENOBLE Alpes /ID# 1140-1058
  • Lille, France, 59037
    • Centre Hospitalier Regional Universitaire de Lille /ID# 1140-0750
  • Nantes, France, 44093
    • CHU de Nantes /ID# 1140-0520
  • Paris, France, 33000
    • Groupe Hospitalier Pitie-Salpetriere /ID# 1140-0918
  • Ile-de-France
    • Paris, Ile-de-France, France, 75010
      • Hopital Saint-Louis - Institut Hematologie Centre Hayem CHU /ID# 1140-0735
  • Meurthe-et-Moselle
    • Vandoeuvre-lès-nancy, Meurthe-et-Moselle, France, 54511
      • Hopital de Brabois /ID# 1140-0775
• Germany
  • Dresden, Germany, 01307
    • Universitaetsklinikum Dresden /ID# 1140-1367
  • Hannover, Germany, 30625
    • Hannover Medical School /ID# 1140-1141
  • Munich, Germany, 80337
    • Dr. Haunerschen Kinderspital /ID# 1140-1142
  • Regensburg, Germany, 93053
    • University Hospital of Regensburg /ID# 1140-1446
  • Baden-Wuerttemberg
    • Stuttgart, Baden-Wuerttemberg, Germany, 70376
      • Robert Bosch Hospital /ID# 1140-1160
  • Niedersachsen
    • Munster, Niedersachsen, Germany, 48149
      • Universitatsklinikum Munster /ID# 1140-1195
• Hungary
  • Budapest, Hungary, 1097
    • St. Laszlo Hospital /ID# 1140-1164
• Italy
  • Bergamo, Italy, 24127
    • ASST Papa Giovanni XXIII /ID# 1140-1231
  • Milan, Italy, 20132
    • Ospedale San Raffaele IRCCS /ID# 1140-0523
  • Torino, Italy, 10124
    • University of Torino /ID# 1140-1268
  • Turin, Italy, 10126
    • Centro Trapianti Cellule Staminali, Ospedale Infantile Regina Margherita /ID# 1140-1156
  • Lazio
    • Rome, Lazio, Italy, 00165
      • IRCCS Ospedale Pediatrico Bambino Gesu /ID# 1140-1150
  • Marche
    • Ancona, Marche, Italy, 60126
      • A.O. Univ. Ospedali Riuniti /ID# 1140-0932
• Japan
  • Kumamoto, Japan, 860-0008
    • Kumamoto Medical Center /ID# 1140-1431
  • Sapporo, Japan, 060-8648
    • Hokkaido University Hospital /ID# 1140-1436
  • Aichi
    • Anjo, Aichi, Japan, 446-8602
      • Anjou Kousei Hospital /ID# 1140-1435
  • Hiroshima
    • Hiroshima-shi, Hiroshima, Japan, 730-8619
      • Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital /ID# 1140-1437
  • Hyogo
    • Kobe-shi, Hyogo, Japan, 650-0047
      • Kobe City Medical Center General Hospital /ID# 1140-1438
    • Nishinomiya-shi, Hyogo, Japan, 663-8501
      • Hyogo College of Medicine College Hospital /Id# 1140-1434
  • Ibaraki
    • Tsukuba-shi, Ibaraki, Japan, 305-8576
      • Duplicate_University of Tsukuba Hospital /ID# 1140-1445
  • Kanagawa
    • Isehara-shi, Kanagawa, Japan, 259-1193
      • Tokai University Hospital /ID# 1140-1444
  • Okayama
    • Kurishiki-shi, Okayama, Japan, 710-8602
      • Duplicate_Kurashiki Central Hospital /ID# 1140-1442
    • Okayama-shi, Okayama, Japan, 700-8558
      • Okayama University Hospital /ID# 1140-1430
  • Osaka
    • Izumi-Shi, Osaka, Japan, 594-1101
      • Osaka Women's and Children's Hospital /ID# 1140-1440
    • Osaka-shi, Osaka, Japan, 545-8586
      • Osaka City University Hospital /ID# 1140-1157
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8677
      • Dup_Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital /ID# 1140-1439
    • Setagaya-ku, Tokyo, Japan, 157-8535
      • National Center for Child Health and Development /ID# 1140-1443
• Korea, Republic of
  • Seoul, Korea, Republic of, 04401
    • SoonChunHyang University Seoul /ID# 1140-1163
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center /ID# 1140-0963
  • Daegu Gwang Yeogsi
    • Daegu, Daegu Gwang Yeogsi, Korea, Republic of, 41944
      • Kyungpook National Univ Hosp /ID# 1140-1153
  • Seoul Teugbyeolsi
    • Seodaemun-gu, Seoul Teugbyeolsi, Korea, Republic of, 03722
      • Yonsei University Health System, Severance Hospital /ID# 1140-0927
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 06351
      • Samsung Medical Center /ID# 1140-0925
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 06591
      • Cath Univ Seoul St Mary's Hosp /ID# 1140-0928
• Singapore
  • Singapore, Singapore, 119228
    • National University Cancer Institute - National University Health System /ID# 1140-1155
  • Singapore, Singapore, 169608
    • Singapore General Hospital /ID# 1140-1162
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic /ID# 1140-0533
  • Barcelona, Spain, 08041
    • Hospital Santa Creu i Sant Pau /ID# 1140-0535
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio /ID# 1140-0863
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia /ID# 1140-1145
• Taiwan
  • Taichung
    • Taichung City, Taichung, Taiwan, 40447
      • China Medical University Hosp /ID# 1140-1199
  • Taipei
    • Taipei City, Taipei, Taiwan, 10002
      • National Taiwan Univ Hosp /ID# 1140-1184
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258-4547
      • Arizona Oncology - Scottsdale - Cancer Transplant Institute Location /ID# 1140-1120
  • California
    • Palo Alto, California, United States, 94304
      • LPCH Stanford /ID# 1140-1128
    • San Francisco, California, United States, 94143
      • Ucsf /Id# 1140-0003
    • Stanford, California, United States, 94305
      • Stanford University/Stanford Cancer Center, Pasteur Drive /ID# 1140-0400
  • Colorado
    • Aurora, Colorado, United States, 80010
      • UCHSC Anschultz Cancer Pavilion /ID# 1140-0068
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center /ID# 1140-1122
  • Florida
    • Miami, Florida, United States, 33136-1096
      • Jackson Memorial Hospital, University of Miami /ID# 1140-0647
    • Orlando, Florida, United States, 32804
      • Florida Hospital Cancer Institute/Adventist Health System/Sunbelt, Inc /ID# 1140-1121
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University, Winship Cancer Institute /ID# 1140-0033
    • Atlanta, Georgia, United States, 30322
      • Emory University/Winship Cancer Institute /ID# 1140-1179
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago /ID# 1140-0126
    • Maywood, Illinois, United States, 60153
      • Loyola University /ID# 1140-0713
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5112
      • Indiana University Melvin and Bren Simon Cancer Center /ID# 1140-0010
  • Kentucky
    • Lexington, Kentucky, United States, 40508-2678
      • University of Kentucky /ID# 1140-1140
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Hospital /ID# 1140-1131
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland /ID# 1140-0205
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center /ID# 1140-0020
    • Boston, Massachusetts, United States, 02115
      • Boston Childrens Hospital /ID# 1140-1615
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute /ID# 1140-0349
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer In /ID# 1140-0130
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota /ID# 1140-0807
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic, Rochester, MN /ID# 1140-0240
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center/ John Theurer Cancer Center /ID# 1140-0343
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of NJ /ID# 1140-0803
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center - Moses Campus /ID# 1140-0120
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital/Weill Cornell Med College /ID# 1140-0200
    • New York, New York, United States, 10021
      • Stony Brook University Medical Center /ID# 1140-0719
    • New York, New York, United States, 10032-1559
      • Columbia University Medical Center, MS-CHONY /ID# 1140-1124
    • New York, New York, United States, 10065
      • Weill Cornell Physicians - Hematologic Malignancies & Bone Marrow Transplant /ID# 1140-0019
    • Rochester, New York, United States, 14642-0001
      • University of Rochester Cancer Center /ID# 1140-0127
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27516
      • University of North Carolina - Lineberger Comprehensive Cancer Center /ID# 1140-1133
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Univ Hosp Cleveland /ID# 1140-0941
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh - UPMC (Hillman Cancer Center) /ID# 1140-0050
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina, MUSC /ID# 1140-0738
  • Tennessee
    • Nashville, Tennessee, United States, 37232-5280
      • Vanderbilt University Medical Center Vanderbilt Ingram Cancer Center /ID# 1140-0024
  • Texas
    • San Antonio, Texas, United States, 78229-3710
      • Methodist San Antonio /ID# 1140-1118
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center /ID# 1140-0404
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University /ID# 1140-1090

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• New onset moderate or severe cGVHD as defined by the 2014 National Institutes of Health (NIH) Consensus Development Project Criteria
• Need for systemic treatment with corticosteroids for cGVHD
• No previous systemic treatment for cGVHD (including extracorporeal photopheresis [ECP])
• Participants may be receiving other immunosuppressants for the prophylaxis or treatment of acute GVHD but if the subject is receiving prednisone for prophylaxis or treatment of acute GVHD it must be at or below 0.5 mg/kg/d
• Age ≥12 years old
• Karnofsky or Lansky (subjects <16 years) performance status ≥60

Key Exclusion Criteria:

• Received any previous systemic treatment for cGVHD with the exception of corticosteroids administered for cGVHD within the 72 hours prior to signing the informed consent form.
• Inability to begin a prednisone dose ≥0.5 mg/kg/d for the treatment of cGVHD
• Any uncontrolled infection or active infection requiring ongoing systemic treatment
• Progressive underlying malignant disease or any post-transplant lymphoproliferative disease
• Known bleeding disorders
• Active hepatitis C virus (HCV) or hepatitis B virus (HBV)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ibrutinib + Prednisone; Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for cytochrome P450 [CYP] inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Drug: ibrutinib; Ibrutinib capsules administered orally daily; Other Names: PCI-32765; IMBRUVICA®; Drug: Prednisone; Prednisone administered daily
Placebo Comparator: Placebo + Prednisone; Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses.	Drug: Prednisone; Prednisone administered daily; Drug: Placebo; Placebo capsules administered orally daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Analysis: Response Rate at 48 Weeks	Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.	48 weeks (Cumulatively up to 30 March 2020)
Final Analysis: Response Rate at 48 Weeks	Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.	48 weeks (Cumulatively up to 12 July 2021)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD	The cumulative incidence of withdrawal of all corticosteroids (95% confidence interval [CI]) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all corticosteroids at given time point. The time to withdrawal of corticosteroids is computed from randomization date to the first date of withdrawal of all corticosteroids for treatment of cGVHD to 0 mg daily for at least 30 days.	Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 30 March 2020)
Final Analysis: Cumulative Incidence of Withdrawal of All Corticosteroids for Treatment of cGVHD	The cumulative incidence of withdrawal of all corticosteroids (95% confidence interval [CI]) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all corticosteroids at given time point. The time to withdrawal of corticosteroids is computed from randomization date to the first date of withdrawal of all corticosteroids for treatment of cGVHD to 0 mg daily for at least 30 days.	Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021)
Primary Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants	The cumulative incidence of withdrawal of all immunosuppressants (95% CI) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all immunosuppressants at a given time point. The time to withdrawal of all immunosuppressants is computed from randomization date to the first date of withdrawal of all immunosuppressants for treatment of cGVHD, sustained for at least 30 days. All immunosuppressants include corticosteroids but they do not include ibrutinib.	Months 3, 6, 9, 12, 15, 18, 21, 24 (cumulatively up to 30 March 2020)
Final Analysis: Cumulative Incidence of Withdrawal of All Immunosuppressants	The cumulative incidence of withdrawal of all immunosuppressants (95% CI) was calculated using SAS lifetest procedure adjusting for competing risks including death, cGVHD progression, relapse of underlying disease, and start of subsequent cGVHD therapy. Data presented are the estimated proportion of participants withdrawing all immunosuppressants at a given time point. The time to withdrawal of all immunosuppressants is computed from randomization date to the first date of withdrawal of all immunosuppressants for treatment of cGVHD, sustained for at least 30 days. All immunosuppressants include corticosteroids but they do not include ibrutinib.	Months 3, 6, 9, 12, 15, 18, 21, 24 (Cumulatively up to 12 July 2021)
Primary Analysis: Response Rate at 24 Weeks	Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a CR or PR at 24 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 24 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.	24 weeks (Cumulatively up to 30 March 2020)
Final Analysis: Response Rate at 24 Weeks	Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a CR or PR at 24 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 24 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.	24 weeks (Cumulatively up to 12 July 2021)
Primary Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits	Clinically meaningful improvement on Lee cGVHD symptom scale was defined as at least a 7-point decrease in Lee Symptom Scale overall summary score on at least 2 consecutive visits, not preceded by progressive disease, relapse of underlying disease or start of subsequent cGVHD treatment. The Lee cGVHD Symptom Scale score has 7 subscales (Skin, Eyes and Mouth, Breathing, Eating and Digestion, Muscles and Joints, Energy, and Mental and Emotional) with ratings as follows: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely, with lower values representing a better outcome. A score is calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. An overall score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores.	Assessed at Weeks 5, 13, 25, 37, 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 30 March 2020)
Final Analysis: Percentage of Participants With Improvement in Overall Score on Lee cGVHD Symptom Scale at Two Consecutive Visits	Clinically meaningful improvement on Lee cGVHD symptom scale was defined as at least a 7-point decrease in Lee Symptom Scale overall summary score on at least 2 consecutive visits, not preceded by progressive disease, relapse of underlying disease or start of subsequent cGVHD treatment. The Lee cGVHD Symptom Scale score has 7 subscales (Skin, Eyes and Mouth, Breathing, Eating and Digestion, Muscles and Joints, Energy, and Mental and Emotional) with ratings as follows: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely, with lower values representing a better outcome. A score is calculated for each subscale by taking the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. An overall score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores.	Assessed at Weeks 5, 13, 25, 37, 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 12 July 2021)
Primary Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days		24 weeks (Cumulatively up to 30 March 2020)
Final Analysis: Percentage of Participants Who Achieved Reduction of Prednisone Dose Level to Less Than 0.15 mg/kg/Day at 24 Weeks Sustained for at Least 30 Days		24 weeks (Cumulatively up to 12 July 2021)
Primary Analysis: Overall Survival (OS)	OS was defined as the time of randomization until the time of death due to any cause, in months.	Median time on study (cumulatively up to 30 March 2020) was 19.8 months and 18.4 months for the Ibrutinib + Prednisone and Placebo + Prednisone arms, respectively.
Final Analysis: OS	OS was defined as the time of randomization until the time of death due to any cause, in months.	Median time on study (cumulatively up to 12 July 2021) was 33.1 months and 32.5 months for the Ibrutinib + Prednisone and Placebo + Prednisone arms, respectively.
Primary Analysis: Duration of Response (DOR) for Participants Who Had PR or CR at Any Time	Response was defined using the NIH Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR was defined as resolution of all manifestations in each organ or site. PR was defined as improvement in at least 1 organ or site without progression in any other organ or site. Duration of response was estimated by Kaplan-Meier methodology.	Response was assessed every 4 weeks from Week 5 through Week 25, Week 37, Week 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 30 March 2020)
Final Analysis: DOR for Participants Who Had PR or CR at Any Time	Response was defined using the NIH Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR was defined as resolution of all manifestations in each organ or site. PR was defined as improvement in at least 1 organ or site without progression in any other organ or site. Duration of response was estimated by Kaplan-Meier methodology.	Response was assessed every 4 weeks from Week 5 through Week 25, Week 37, Week 49, 30 days after the last dose of study drug, and then every 12 weeks of follow-up until progressed disease. (Cumulatively up to 12 July 2021)
Primary Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone	AE: any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization >24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity was graded according to the Common Terminology Criteria for Adverse Events version 4.03 (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5=death). Treatment-related events are those that were possibly related or related to study treatment per investigator's judgment. Treatment emergent AEs (TEAEs) occurred from the first dose of study drug up to 30 days after the last dose of study drug.	From first dose of study drug through the end of treatment plus 30 days. As of data cutoff (cumulatively up to 30 March 2020), median ibrutinib treatment duration was 5.4 months and the median placebo treatment duration was 6.4 months.
Final Analysis: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs Placebo in Combination With Prednisone	AE: any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. SAE: any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization >24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. Severity was graded according to the Common Terminology Criteria for Adverse Events version 4.03 (grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening, grade 5=death). Treatment-related events are those that were possibly related or related to study treatment per investigator's judgment. Treatment emergent AEs (TEAEs) occurred from the first dose of study drug up to 30 days after the last dose of study drug.	From first dose of study drug through the end of treatment plus 30 days. As of data cutoff (cumulatively up to 12 July 2021), median ibrutinib treatment duration was 5.4 months and the median placebo treatment duration was 6.4 months.

Collaborators and Investigators

• Sponsor: Pharmacyclics LLC.
• Collaborators: Janssen Research & Development, LLC

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2017
• Primary Completion (Actual): March 27, 2020
• Study Completion (Actual): July 12, 2021

Study Registration Dates

• First Submitted: October 25, 2016
• First Submitted That Met QC Criteria: November 7, 2016
• First Posted (Estimate): November 9, 2016

Study Record Updates

• Last Update Posted (Actual): March 30, 2023
• Last Update Submitted That Met QC Criteria: March 28, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: chronic; Pharmacyclics; PCYC; Ibrutinib; refractory; GVHD; IMBRUVICA; immunology; Corticosteroids; prednisone; graft versus host disease; chronic graft versus host disease; Steroid dependent; PCYC1140; PCYC1140IM; 1140; PCI32765; new onset graft versus host disease; INTEGRATE
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisone
• Other Study ID Numbers: PCYC-1140-IM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Requests for access to individual participant data from clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access (YODA) Project site at the following link.

Drug and device information, study documents

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