Chronic Graft-versus-host-disease
Conditions
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.
Interventions
DRUGIbrutinib
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.
DRUGRituximab
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.
Sponsors
Dartmouth-Hitchcock Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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).) 2. Chronic GVHD that is confirmed by clinical assessment and/or biopsy. 3. Either steroid-refractory or steroid-dependent cGVHD. 4. Karnofsky performance status ≥ 60.
Exclusion criteria
1. History of treatment with a tyrosine kinase inhibitor (eg, imatinib) or other moderate-to-significant Cyclophilin A4 inhibitor within 2 weeks of enrollment. 2. Renal insufficiency as follows: creatinine \> 2.5 mg/deciliters (dL) or Creatinine Clearance \< 30 ml/min. 3. Hepatic insufficiency as follows: serum bilirubin \>3 mg/dL or transaminitis \>3x upper limit of normal (ULN) (unless deemed due to GVHD). 4. History of cardiac dysrhythmias or known cardiovascular disease without formal Cardiology clearance. 5. History of cerebro-vascular accident or intracranial hemorrhage within 6 months prior to enrollment. 6. History of non-intracranial hemorrhage and/or coagulopathy without formal Coagulation clearance. 7. 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. 8. History of other hematologic malignancy. 9. History of human immunodeficiency virus (HIV). 10. History of active hepatitis B virus (HBV) or hepatitis C virus (HCV) without formal Infectious Disease clearance. 11. Patients incapable of complying with routine follow up schedule or unable to be compliant with study therapy. 12. Active or within 3 months use of prohibited medications or substances (e.g., illicit drugs).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
All participants were recruited at a single site, Dartmouth-Hitchcock Norris Cotton Cancer Center in Lebanon New Hampshire. Recruitment extended throughout the life of the study from 4/11/2019 to 07/22/2021.
Participants by arm
| Arm | Count |
|---|---|
| Ibrutinib Plus 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). | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Ibrutinib Plus Rituximab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 2 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 0 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
Primary
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.
Time frame: Start of treatment through Week 4 of treatment
Population: 0 patients analyzed. 1 patient withdrawn early and 1 patient not complaint with study procedures.
Secondary
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).
Time frame: 6 weeks, 3 months, and 6 months after initiation of treatment
Population: Subject 1 off study before 6 week assessment due to study drug possibly related rash SAE.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibrutinib Plus Rituximab | Assess the Response Rate of cGVHD to Treatment With Ibrutinib Plus Rituximab | 0 Participants |
Secondary
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.
Time frame: 6 weeks, 3 months, and 6 months after initiation of treatment
Population: Laboratory correlates for this study were not processed or analyzed for any subject enrolled onto this study.