Ibrutinib Plus Rituximab for cGVHD Following Allo-SCT

Phase 1

Terminated

Conditions: Chronic Graft-versus-host-disease

Interventions: Drug: Ibrutinib
Drug: Rituximab

Registration Number: NCT03689894

Lead Sponsor: Dartmouth-Hitchcock Medical Center

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 2

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ibrutinib plus Rituximab	Rituximab	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).
Ibrutinib plus Rituximab	Ibrutinib	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).

Primary Outcome Measures

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

Secondary Outcome Measures

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