Ibrutinib Plus Rituximab for cGVHD Following Allo-SCT

Study Overview
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Brief Summary
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Allogeneic stem cell transplant is used to treat a variety of blood cancers. However, graft-versus-host disease (GVHD) is a common condition that may occur after transplant. GVHD happens when the donor cells attack and damage the recipients' tissue. The standard medication to treat chronic graft-versus-host-disease (cGVHD) is corticosteroids. However, there are long-term side effects of steroid therapy, including risk of infection, bone loss and other health problems. In addition, some patients with cGVHD do not respond to standard steroid therapy. In these cases, medications to suppress the immune system may be used. The purpose of this study is to learn about the effects, both good and bad, of combining the drugs ibrutinib and rituximab for the treatment of cGVHD. Ibrutinib is Food and Drug Administration (FDA)-approved for the treatment of cGVHD which has not responded to steroid therapy. Rituximab is an investigational drug, which means it is not FDA approved for this particular use. Rituximab is currently approved for treatment of Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), and other conditions, but is not FDA approved for the treatment of cGVHD. However, rituximab has been used in a clinic setting for the treatment of cGVHD in a number of patients over the past few years, and has generally been well tolerated and shown some benefit. The combination of ibrutinib and rituximab is being studied in the treatment of certain types of lymphoma and chronic leukemia, but it has not yet been combined for patients with cGVHD. Because ibrutinib is not approved for this use when combined with rituximab, it is considered investigational in this study. In this form, the term study drug refers to ibrutinib and rituximab. This study will involve people who have chronic GVHD, have previously taken corticosteroids, and have either not benefited from treatment with corticosteroids or have been unable to successfully taper off steroids.

Official Title
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Combination Ibrutinib and Rituximab for the Treatment of Chronic Graft-Versus-Host Disease Following Allogeneic Stem Cell Transplant

Conditions
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Chronic Graft-versus-host-disease

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥18 years old who are recipients of an allogeneic bone marrow, cord blood or peripheral blood stem cell transplant. (There will be no restrictions based upon underlying disease, donor source, degree of human leukocyte antigen (HLA) match, intensity of pre-transplant conditioning regimen or use of prior donor lymphocyte infusion(s).) Chronic GVHD that is confirmed by clinical assessment and/or biopsy. Either steroid-refractory or steroid-dependent cGVHD. Karnofsky performance status ≥ 60. Exclusion Criteria: History of treatment with a tyrosine kinase inhibitor (eg, imatinib) or other moderate-to-significant Cyclophilin A4 inhibitor within 2 weeks of enrollment. Renal insufficiency as follows: creatinine > 2.5 mg/deciliters (dL) or Creatinine Clearance < 30 ml/min. Hepatic insufficiency as follows: serum bilirubin >3 mg/dL or transaminitis >3x upper limit of normal (ULN) (unless deemed due to GVHD). History of cardiac dysrhythmias or known cardiovascular disease without formal Cardiology clearance. History of cerebro-vascular accident or intracranial hemorrhage within 6 months prior to enrollment. History of non-intracranial hemorrhage and/or coagulopathy without formal Coagulation clearance. Uncontrolled infections not responsive to antibiotics, anti-viral medicines, or anti-fungal medicines; or infection requiring systemic treatment that was completed ≤14 days before enrollment. History of other hematologic malignancy. History of human immunodeficiency virus (HIV). History of active hepatitis B virus (HBV) or hepatitis C virus (HCV) without formal Infectious Disease clearance. Patients incapable of complying with routine follow up schedule or unable to be compliant with study therapy. Active or within 3 months use of prohibited medications or substances (e.g., illicit drugs).

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: Ibrutinib plus Rituximab<br>Rituximab *375 milligrams (mg) per meter squared intravenous infusion weekly for 4 (may repeat 8 weeks after initial therapy, if suboptimal response) Ibrutinib 420 mg (140 mg capsule x3) by mouth daily May be given beyond 3-6 months (for maintenance). | Drug: Ibrutinib<br>* Subjects will receive oral (PO) Ibrutinib 140 mg once daily with Rituximab 375 mg per meter squared IV weekly x4 (with pre-medications and infusion procedure as per standard protocol) Rituximab Pre-medications:Acetaminophen 650 mg PO; Diphenhydramine 25 mg PO/IV; Dexamethasone 20 mg IV. If no adverse events >Grade 3+ are noted after 1 week, the Ibrutinib dose schedule will be increased to 280 mg daily. If no adverse events >Gr3+ are noted after an additional 1 week, the Ibrutinib dose will be increased to 420 mg daily.<br>Drug: Rituximab<br>* Subject will receive an intravenous infusion of 375mg per meter squared weekly for 4 weeks, which may be repeated 8 weeks after initial therapy if only a suboptimal response is achieved.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate Dose-limiting Toxicities Experienced in Subjects Treated With Ibrutinib Plus Rituximab | During dose escalation, subjects will be assessed for dose-limiting toxicities at each dose level. | Start of treatment through Week 4 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the Response Rate of cGVHD to Treatment With Ibrutinib Plus Rituximab | Response rate of clinically significant GVHD will be assessed using NIH criteria (from 2014 NIH Consensus Development Project). | 6 weeks, 3 months, and 6 months after initiation of treatment | 
| Identify Relevant Laboratory Correlates Underlying Clinical Response, or Lack Thereof. | Plasma ST2 and CD4CD25FOXp3 correlates will be measured at identified intervals to determine if either correlate demonstrates an affect on clinical response. | 6 weeks, 3 months, and 6 months after initiation of treatment |