A Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Participants With Steroid Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD)

A Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib in Subjects With Steroid Dependent/Refractory Chronic Graft Versus Host Disease (cGVHD)

The purpose of this study is to evaluate efficacy of ibrutinib in Japanese participants with steroid dependent/refractory chronic graft versus host disease (cGVHD) by measuring overall cGVHD response (complete response [CR] and partial response [PR] defined by National Institutes of Health [NIH] consensus development project criteria [2014]).

Study Overview

• Status: Completed
• Conditions: Graft vs Host Disease
• Intervention / Treatment: Drug: Ibrutinib

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Anjo-shi, Japan, 446-8602
    • Anjo Kosei Hospital
  • Bunkyo ku, Japan, 113 8677
    • Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital
  • Hiroshima, Japan, 730-8619
    • Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital
  • Isehara, Japan, 259-1193
    • Tokai University Hospital
  • Izumi, Japan, 594-1101
    • Osaka Women's and Children's Hospital
  • Kobe City, Japan, 650 0047
    • Kobe City Medical Center General Hospital
  • Kumamoto-shi, Japan, 860-0008
    • National Hospital Organization Kumamoto Medical Center
  • Kurashiki, Japan, 710-8602
    • Kurashiki Central Hospital
  • Maebashi, Japan, 371-0821
    • Gunmaken Saiseikai Maebashi Hospital
  • Nagoya, Japan, 453-8511
    • Japanese Red Cross Nagoya Daiichi Hospital
  • Nishinomiya, Japan, 663-8501
    • The Hospital of Hyogo College of Medicine
  • Okayama, Japan, 700 8558
    • Okayama University Hospital
  • Osaka, Japan, 545 8586
    • Osaka City University Hospital
  • Sapporo-shi, Japan, 060-8648
    • Hokkaido University Hospital
  • Setagaya Ku, Japan, 157 8535
    • National Center for Child Health and Development

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Steroid dependent/refractory chronic graft versus host disease (cGVHD) defined as modified National Institutes of Health (NIH) criteria (2014) below at any time post-hematopoietic cell transplant (post-HCT): a) Dependent disease, defined as, when glucocorticoid (prednisolone doses greater than or equal to [>=] 0.25 milligram per kilogram per day (mg/kg/day)or >=0.5 milligram per kilogram (mg/kg) every other day) are needed to prevent recurrence or progression of manifestations as demonstrated by unsuccessful attempts to taper the dose to lower levels on at least 2 occasions, separated by at least 8 weeks. In case of inability to taper the dose to less than or equal to (<=)0.25 mg/kg/day or <=0.5 mg/kg every other day (prednisolone doses) due to recurrence or progression of cGVHD manifestations, it is considered as steroid-dependent disease if the lowest tapering dose of the second occasion is equal or higher than the lowest tapering dose of the first occasion; b) Refractory disease, defined as, when cGVHD manifestations progress despite the use of a regimen containing glucocorticoid (prednisolone at >=1 mg/kg/day for at least 1 week) or persist without improvement despite continued treatment with glucocorticoid (prednisolone at >=0.5 mg/kg/day or 1 mg/kg every other day) for at least 4 weeks
• Participants must be receiving baseline systemic glucocorticoid therapy for cGVHD at study entry. The dose of steroids must be stable for 14 days prior to starting ibrutinib
• At the time of trial enrollment, participants may be receiving other immunosuppressive therapies in addition to glucocorticoids. Immunosuppressant doses must be stable for 14 days prior to starting ibrutinib
• Clinically stable or worsening cGVHD for a minimum of 14 days between screening and Day 1 cGVHD response assessment
• Karnofsky or Lansky (participants less than [<]16 years) performance status >=60

Exclusion Criteria:

• Active acute graft versus host disease (GVHD)
• More than 3 previous systemic treatments for cGVHD. Treatment with glucocorticoids is considered a treatment for cGVHD and should be included in determining the number of previous treatments
• History of treatment with a tyrosine kinase inhibitor (example [e.g.] imatinib), purine analogs, or other cancer chemotherapy in the 4 weeks prior to starting ibrutinib. Participants may have received ibrutinib pre-transplant for other reasons besides cGVHD such as for the treatment of leukemia or lymphoma
• History of treatment with monoclonal T and B cell antibodies in the 8 weeks prior to starting ibrutinib
• Vaccinated with live, attenuated vaccines within 4 weeks of first dose of ibrutinib

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ibrutinib; Participants will receive 420 milligram (mg) oral ibrutinib once daily starting on Week 1 Day 1, unless they have intervening unacceptable toxicity or meet other criteria for participants discontinuation.	Drug: Ibrutinib; Participants will receive 420 mg (3 * 140 mg capsules) oral ibrutinib once daily starting on Week 1 Day 1, unless they have intervening unacceptable toxicity or meet other criteria for participants discontinuation.; Other Names: PCI-32765; JNJ-54179060

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	ORR is defined as the percentage of participants who achieve complete response (CR) or partial response (PR) in the absence of new therapy for chronic graft versus host disease (cGVHD) and absence of progression of underlying disease or death based on the National Institutes of Health (NIH) Consensus Development Project Criteria (2014). 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; and chronic graft versus host disease (cGVHD) progression is defined as clinically meaningful worsening in 1 or more organs regardless of improvement in other organs.	Up to 3 year 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sustained Response Rate	Sustained response rate was defined as percentage of participants with NIH defined CR or PR that was sustained for at least 20 weeks. 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.	Up to 3 year 6 months
Duration of Response (DOR)	DOR is defined as the duration from the date of initial response (CR or PR) to the date of progressive cGVHD or death, whichever occurred first. 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; and cGVHD progression is defined as clinically meaningful worsening in 1 or more organs regardless of improvement in other organs.	Up to 3 year 6 months
cGVHD Response Rate at Each Timepoints	cGVHD response rate was defined as percentage of participants with NIH defined CR or PR at each timepoint. 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.	Weeks 5, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157
Change in the Amount of Corticosteroid Required Over Time	Change in the amount of corticosteroid required over time was reported.	Baseline, Weeks 24, 48, 96, and 144
Percentage of Participants With Overall Improvement in Lee cGVHD Symptom Scale Score	Percentage of participants with overall improvement in Lee cGVHD symptom scale score was reported. Lee cGVHD symptom scale is a patient-reported symptom scale used to measure symptom burden and 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 was 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 with a higher score indicating worse symptoms. An overall score was calculated as the average of these 7 subscales if at least 4 subscales had valid scores. A change of greater than or equal to (>=) 7 points on the Lee cGVHD symptom scale overall score was considered significant and relates to improvement in quality of life (QoL).	Up to 3 year 6 months
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	An AE is any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs are adverse events with onset during the treatment phase or that were a consequence of a preexisting condition that has worsened since baseline, and occurred during treatment or within 30 days following the last dose of study treatment, or any adverse event that was considered study treatment-related regardless of the start date of the event.	Up to 3 year 6 months
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC [0-last]) of Ibrutinib	AUC(0-last) is defined as area under the plasma concentration-time curve from time zero to time of last measurable concentration of ibrutinib.	Day 1 of Weeks 1 and 2
Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC [0-24]) of Ibrutinib	AUC(0-24) is defined as area under the plasma concentration-time curve from time zero to 24 hours of ibrutinib.	0 to 24 hours (Day 1 of Weeks 1 and 2)
Maximum Observed Plasma Concentration (Cmax) of Ibrutinib	Cmax is defined as maximum observed plasma concentration of ibrutinib.	Day 1 of Weeks 1 and 2
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ibrutinib	Tmax is defined as time to reach the maximum observed plasma concentration of ibrutinib.	Day 1 of Weeks 1 and 2
Elimination Half-Life (t1/2) of Ibrutinib	T1/2 is defined as elimination half-life of ibrutinib.	Day 1 of Weeks 1 and 2
Apparent Clearance (CL/F) of Ibrutinib	CL/F is defined as apparent clearance of ibrutinib.	Day 1 of Weeks 1 and 2
Apparent Volume of Distribution (Vd/F) of Ibrutinib	Vd/F is defined as apparent volume of distribution of ibrutinib.	Day 1 of Weeks 1 and 2
Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Ibrutinib	AUC(0-infinity) is defined as area under the plasma concentration-time curve from time zero to infinite time of ibrutinib.	Day 1 of Weeks 1 and 2
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration (AUC [0-last]) of PCI-45227	AUC(0-last) is defined as area under the plasma concentration-time curve from time zero to time of last measurable concentration of PCI-45227.	Day 1 of Weeks 1 and 2
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC [0-24]) of PCI-45227	AUC(0-24) is defined as area under the plasma concentration-time curve from time zero to 24 hours of PCI-45227.	0 to 24 hours (Day 1 of Weeks 1 and 2)
Maximum Observed Plasma Concentration (Cmax) of PCI-45227	Cmax is defined as maximum observed plasma concentration of PCI-45227.	Day 1 of Weeks 1 and 2
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PCI-45227	Tmax is defined as time to reach the maximum observed plasma concentration of PCI-45227.	Day 1 of Weeks 1 and 2
Elimination Half-Life (t1/2) of PCI-45227	T1/2 is defined as elimination half-life of PCI-45227.	Day 1 of Weeks 1 and 2
Apparent Clearance (CL/F) of PCI-45227	CL/F is defined as apparent clearance of PCI-45227.	Day 1 of Weeks 1 and 2
Apparent Volume of Distribution (Vd/F) of PCI-45227	Vd/F is defined as apparent volume of distribution of PCI-45227.	Day 1 of Weeks 1 and 2
Area Under the Plasma Concentration-time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of PCI-45227	AUC(0-infinity) is defined as area under the plasma concentration-time curve from time zero to infinite time of PCI-45227.	Day 1 of Weeks 1 and 2

Collaborators and Investigators

• Sponsor: Janssen Pharmaceutical K.K.
• Investigators: Study Director: Janssen Pharmaceutical K.K., Japan Clinical Trial, Janssen Pharmaceutical K.K.

Publications and helpful links

General Publications

• Doki N, Toyosaki M, Shiratori S, Osumi T, Okada M, Kawakita T, Sawa M, Ishikawa T, Ueda Y, Yoshinari N, Nakahara S. An Open-Label, Single-Arm, Multicenter Study of Ibrutinib in Japanese Patients With Steroid-dependent/Refractory Chronic Graft-Versus-Host Disease. Transplant Cell Ther. 2021 Oct;27(10):867.e1-867.e9. doi: 10.1016/j.jtct.2021.05.019. Epub 2021 Jun 6.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2018
• Primary Completion (Actual): November 29, 2021
• Study Completion (Actual): November 29, 2021

Study Registration Dates

• First Submitted: March 16, 2018
• First Submitted That Met QC Criteria: March 16, 2018
• First Posted (Actual): March 22, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 31, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organizing Pneumonia; Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchiolitis Obliterans Syndrome; Graft vs Host Disease; Tyrosine Kinase Inhibitors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Ibrutinib
• Other Study ID Numbers: CR108443; 54179060GVH3001 (Other Identifier: Janssen Pharmaceutical K.K., Japan)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes