Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Chronic Graft Versus Host Disease

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and clinical efficacy of ibrutinib in subjects with steroid dependent or refractory Chronic Graft Versus Host Disease.

Official Title
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A Multicenter Open-Label Phase 1b/2 Study of Ibrutinib in Steroid Dependent or Refractory Chronic Graft Versus Host Disease

Conditions
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Graft Versus 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 or refractory classic chronic GVHD disease. No more than 3 previous treatments for cGVHD. Receiving baseline systemic glucocorticoid therapy (at stable dose) for cGVHD at study entry. Men and women ≥18 years old. Karnofsky performance status ≥60. Exclusion Criteria: Known or suspected active acute GVHD. Current treatment with sirolimus AND either cyclosporine or tacrolimus. History of treatment with a tyrosine kinase inhibitor (eg, imatinib), purine analogs or other cancer chemotherapy in the 4 weeks prior to starting study drug. Currently active, clinically significant cardiovascular disease. Uncontrolled infections not responsive to antibiotics, antiviral medicines, or antifungal medicines or a recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug. Progressive underlying malignant disease including post-transplant lymphoproliferative disease. History of other malignancy (not including the underlying malignancy that was the indication for transplant) Concomitant use of warfarin or other Vitamin K antagonists Known bleeding disorders or hemophilia. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Concurrent use of a strong cytochrome P450(CYP) 3A inhibitor.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Dose Level 1<br>Subjects receive daily dose of 420 mg of Ibrutinib capsules | Drug: Ibrutinib<br> <br> * Other names: PCI32765;|
| Experimental: Phase 1b: Dose Level 2<br>Subjects receive daily dose of 280 mg of Ibrutinib capsules | Drug: Ibrutinib<br> <br> * Other names: PCI32765;|
| Experimental: Phase 1b: Dose Level 3<br>Subjects receive daily dose of 140 mg of Ibrutinib capsules | Drug: Ibrutinib<br> <br> * Other names: PCI32765;|
| Experimental: Phase 2<br>Subjects receive daily dose of recommended phase 2 dose | Drug: Ibrutinib<br> <br> * Other names: PCI32765;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: To Evaluate the Safety and Tolerability of Ibrutinib in Steroid Dependent/Refractory cGVHD. | Number of participants with dose-limiting toxicities as a measure of safety profile to determine recommended dose of ibrutinib | 28 treatment days after last subject enrolled in Phase 1 dose level(s). | 
| Phase 2: Overall Response Rate as the Percentage of Participants With Response | Overall Response Rate is defined as the proportion of subjects who achieved complete response (CR) or partial response (PR). Response criteria are based on NIH cGVHD Response assessment (Pavletic 2006; Measurement of Therapeutic Response, ASBMT Web site). | Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Response Rate as the Percentage of Participants With Sustained Response | For subjects who achieved an NIH-defined CR or PR, the proportion of subjects who achieved CR or PR that was sustained for at least 20 weeks (140 days). Intermittent SD was also acceptable. | Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months. | 
| To Evaluate the Clinical Efficacy of Ibrutinib in Steroid Dependent/Refractory cGVHD by Measuring: Duration of Response (DOR) | For subjects who achieved an NIH-defined CR or PR, the interval between the date of initial documentation of a response and the date of first documented evidence of PD, death, or date of censoring if applicable. | Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months. | 
| Corticosteroid Requirement Changes Over Time | Average daily corticosteroid dose assessed each week. | Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months. | 
| Percentage of Participants With Overall Improvement in Lee cGVHD Symptom Summary Score | Subject reported improvement in symptom burden. The symptom burden will be measured according to the Lee cGVHD Symptom Scale. A change in >7 points on the Lee cGVHD Symptom Scale will be considered significant and relates to improvement in quality of life. 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. A total summary score is calculated as the average of these 7 subscales if at least 4 subscales have valid scores. There are 7 subscales (Skin, Energy, Lung, Eye, Nutrition, Mouth and Psychological) with ratings as follow: 0- Not at all, 1- Slightly, 2 Moderately, 3 Quite a bit, 4-Extremely; with a lower values representing a better outcome. | Analysis was conducted with the data extraction date of 15 Sep 2017, with a median follow-up time of 25.56 months. | 
| Phase 2b: To Evaluate the Safety and Tolerability of Ibrutinib in Steroid Dependent/Refractory cGVHD | Number of Participants With Adverse Events as a Measure of Safety and Tolerability of Ibrutinib | From first dose with study drug until 30 days after the last dose of study drug, up to 36.7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCYC1129, PCYC1129CA, 1129, Ibrutinib, PCI32765, IMBRUVICA, Pharmacyclics, PCYC, GVHD, Steroid dependent, refractory, chronic, graft versus host disease, chronic graft versus host disease, immunology