Ibrutinib and Rituxan for Chronic GVHD

Study Overview
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Brief Summary
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This is a phase II trial evaluating the safety and efficacy of the combination of Ibrutinib and Rituximab as primary treatment of chronic GVHD. We plan to enroll 35 patients on this study. Patients will be formally monitored monthly for 12 months to evaluate for outcome and safety endpoints. All other assessments will be done at the physician's discretion or institutional standards. All patients, responders and treatment failures, will be followed for a period of one year from the time of initiation of therapy. The primary endpoint will be the proportion of patients that are alive and off all systemic IST at 12 months following initiation of treatment.

Official Title
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Phase II Trial Evaluating the Safety and Efficacy of Combined CD20- and BTK-Targeted B Cell Depleting Therapy With Rituximab and Ibrutinib in the Primary Treatment of Chronic Graft-Versus-Host Disease

Conditions
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Graft Vs Host Disease

Intervention / Treatment
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* Drug: Rituximab
* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: First episode of systemic immunosuppression-requiring cGVHD, defined as classic or overlap cGVHD by the NIH consensus criteria. Previously untreated cGVHD, defined by having received <10 days of corticosteroids or alternative systemic immunosuppressive agent started specifically for a new diagnosis of cGVHD. KPS 70% or greater Exclusion Criteria: Late persistent or recurrent acute GVHD Active uncontrolled infection History of HIV infection; active HBV or HCV infection Inability to tolerate oral medications Progressive or recurrent malignancy following allogeneic transplant Exposure to BTK inhibitor following transplant Received prior treatment with ECP for cGVHD

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab + Ibrutinib<br>Eligible patients will be those with a first episode of symptomatic cGVHD, requiring systemic immunosuppression for control of symptoms. Following study entry, patients will be started on rituximab plus ibrutinib. | Drug: Rituximab<br>* Rituximab is given IV weekly x 4 weeks (to be started on study day 7 ± 3 days), then IV q3months x 4 doses (months 4, 7, 10, 13).<br>Drug: Ibrutinib<br>* Ibrutinib is given orally every day (28-day cycles) for a total of 12 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of patients who remain off immunosuppressive therapy at 8 weeks after the initiation of treatment. | The primary objective is to evaluate the efficacy of the combination of rituximab and ibrutinib versus the historical experience with rituximab alone in the upfront treatment of cGVHD. Patients will be followed for 12 months following the initiation of treatment to see if they remain off immunosuppressive therapy for at least 8 weeks. | 12 months following initiation of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of patients who respond to treatment assessed by NIH Response Criteria Working Group Report. | To estimate chronic GVHD response (CR + PR, both individual organ response and overall response, according to 2014 NIH Response Criteria Working Group Report) | 12 months following initiation of treatment | 
| The total cumulative steroid exposure measured by total milligrams received by each patient. | To estimate cumulative steroid exposure (total mg methylprednisolone or equivalent) | 12 months following initiation of treatment | 
| How long it takes for patients to discontinue treatment defined as the date all systemic immunosuppressive therapy is discontinued after resolution of GVHD. | To estimate time to discontinuation of systemic immunosuppression (defined as the date that all systemic IST has been discontinued after resolution of all reversible manifestations of cGVHD). | 12 months following initiation of treatment | 
| How many patients are still alive without the requirement for second-line cGVHD therapy measured by overall survival at 12 months following the initiation of treatment. | To estimate failure-free survival (defined as being alive without the requirement for second-line cGVHD therapy). | 12 months following initiation of treatment | 
| How many patients have not relapsed measured by progression-free survival at 12 months following the initiation of treatment. | To estimate non-relapse mortality | 12 months following initiation of treatment | 
| How many patients have not died measured by overall survival at 12 months following the initiation of treatment. | To estimate overall survival | 12 months following initiation of treatment | 
| Number of patients with treatment-related adverse events grade 3 or greater as assessed by CTCAE v.4.0. | To estimate the incidence of grade 3 or greater adverse events, possibly or probably related to either ibrutinib and/or rituximab. | 12 months following initiation of treatment | 
| Number of patients with treatment-related adverse events total as assessed by CTCAE v.4.0. | To evaluate the safety and tolerability of combination of rituximab and ibrutinib versus the historical experience with rituximab alone in the upfront treatment of cGVHD. | 12 months following initiation of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ibrutinib, rituximab, cGVHD, chronic GVHD