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

Study Overview
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Brief Summary
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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]).

Official Title
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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)

Conditions
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Graft vs Host Disease

Intervention / Treatment
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* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib<br>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<br>* 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.<br>* Other names: JNJ-54179060;|

What is the study measuring?
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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 |