Ibrutinib for Preventing Graft-versus-Host Disease
Recruiting in Palo Alto (17 mi)
Overseen byMohamed A. Kharfan Dabaja, MD, MBA
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Mayo Clinic
Must not be taking: Warfarin, Strong CYP3A inhibitors
Disqualifiers: Uncontrolled acute GVHD, Active infections, Stroke, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Approved in 4 Jurisdictions
Trial Summary
What is the purpose of this trial?This phase II trial tests how well ibrutinib works in preventing chronic graft-versus-host disease (GVHD) in patients undergoing donor (allogeneic) hematopoietic cell transplantation (HCT). An allogeneic hematopoietic cell transplantation (allo-HCT) is a treatment in which a person receives blood-forming stem cells (cells from which all blood cells develop) from a genetically similar, but not identical donor. When healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets. However, sometimes the transplanted cells from a donor can attack the body's normal cells (called GVHD). Giving ibrutinib after the transplant may stop that from happening. Ibrutinib is in a class of medications called kinase inhibitors. It works by blocking a protein in the blood called Bruton's tyrosine kinase (BTK). By blocking BTK, ibrutinib inhibits certain immune cells that play a role in cGVHD. Giving ibrutinib after an allo-HCT may prevent the development of chronic GVHD.
Do I need to stop my current medications for the trial?
The trial protocol does not specify if you need to stop your current medications. However, you cannot take certain medications like strong CYP3A inhibitors or anticoagulants like warfarin while participating in the trial. It's best to discuss your current medications with the trial team.
What data supports the effectiveness of the drug Ibrutinib for preventing graft-versus-host disease?
Ibrutinib has been shown to be effective in treating chronic graft-versus-host disease (cGVHD) in patients who did not respond to other treatments, with studies demonstrating high rates of sustained responses and manageable side effects. Additionally, research in mice has shown that Ibrutinib can significantly reduce the severity of cGVHD, suggesting its potential as a preventive treatment.
12345Is ibrutinib safe for preventing graft-versus-host disease?
Ibrutinib has been approved for use in both adults and children with graft-versus-host disease, but it comes with warnings about potential risks like bleeding, infections, heart problems, and other side effects such as muscle pain, fever, and diarrhea. It's important for participants to be aware of these risks and discuss them with their healthcare provider.
13467How does the drug ibrutinib differ from other treatments for preventing graft-versus-host disease?
Ibrutinib is unique because it targets both B cells and T cells by inhibiting Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK), which are crucial in the development of chronic graft-versus-host disease (cGVHD). This dual action helps prevent and treat cGVHD more effectively than treatments that do not target these pathways.
12347Eligibility Criteria
This trial is for patients who've had a donor stem cell transplant to treat conditions like cancer. It's designed to see if taking Ibrutinib after the transplant can prevent chronic graft-versus-host disease, which happens when donor cells attack the patient's body.Inclusion Criteria
Provide written informed consent
Hemoglobin must be ≥ 8.0 g/dL (untransfused) (obtained ≤ 7 days prior to registration)
I had my transplant between 50 and 110 days ago.
+13 more
Exclusion Criteria
Nursing persons
Active hepatitis B or C infection
Patients known to have tested positive on HIV antibody test
+18 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive ibrutinib orally once daily on days 1-30 of each cycle. Cycles repeat every 30 days for up to 12 cycles.
12 months
Monthly visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, including the incidence of chronic GVHD and other outcomes.
12 months
Quarterly visits (in-person)
Participant Groups
The study is testing Ibrutinib, a kinase inhibitor that blocks proteins involved in immune responses that could lead to chronic GVHD. The goal is to determine if it can help prevent this condition post-transplant.
1Treatment groups
Experimental Treatment
Group I: Prevention (ibrutinib)Experimental Treatment2 Interventions
Patients receive ibrutinib PO QD on days 1-30 of each cycle. Cycles repeat every 30 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo an echocardiography prior to registration on study.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo Clinic in FloridaJacksonville, FL
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Who Is Running the Clinical Trial?
Mayo ClinicLead Sponsor
References
FDA review summary of patient-reported outcome results for ibrutinib in the treatment of chronic graft versus host disease. [2021]On August 2, 2017, the Food and Drug Administration approved ibrutinib (IMBRUVICA) for the treatment of patients with chronic graft versus host disease (cGVHD) after the failure of one or more lines of systemic therapy. The approval was based on results from a single-arm, multicenter trial that enrolled patients with refractory cGVHD. This paper describes the FDA review of patient-reported outcomes (PRO) data from Study PCYC-1129-CA and the decision to incorporate descriptive PRO data in the FDA label to support the primary clinician-reported outcome results.
Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. [2021]Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity. Here, we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models, a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans (BO). In the T cell-mediated sclerodermatous cGVHD model, ibrutinib treatment delayed progression, improved survival, and ameliorated clinical and pathological manifestations. In the alloantibody-driven cGVHD model, ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Furthermore, ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD. Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent, warranting consideration for cGVHD clinical trials.
Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice. [2021]Bruton's Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.
Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study. [2023]To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD).
Ibrutinib for the treatment of patients with chronic graft-versus-host disease after failure of one or more lines of systemic therapy. [2021]Chronic graft-versus-host disease (cGvHD) is a grave complication of allogeneic hematopoietic cell transplantation (alloHCT). Despite the use of prophylactic regimens for cGvHD, a significant proportion of patients develop cGvHD following alloHCT. The standard first-line therapy for cGvHD is high-dose corticosteroids. However, roughly 50% of patients will exhibit steroid-refractory or steroid-dependent cGvHD, which increases the risk of non-relapse mortality. Ibrutinib was approved by the U.S. Food and Drug Administration (FDA) in August 2017 for the treatment of cGvHD after failure of one or more lines of systemic therapy. The approval was based on a study that demonstrated high rates of sustained responses and manageable toxicities in patients with steroid-refractory or -dependent cGvHD. In this review, we address the mechanisms of action of ibrutinib in cGvHD, as well as preclinical and clinical data supporting its use in patients with this important post-transplant complication.
Drug Receives New Indication for Pediatric Graft-Versus-Host Disease. [2023]Ibrutinib (Imbruvica) has received a new indication for the treatment of graft-versus-host disease in pediatric patients at least one year of age when one or more systemic therapies have failed.The product's labeling warns of the risk of hemorrhage, infections, cardiac arrythmias, cardiac failure and sudden death, hypertension, cytopenia, secondary primary malignancies, tumor lysis syndrome, and embryo-fetal toxicity.The most common adverse effects include laboratory abnormalities, musculoskeletal pain, pyrexia, pneumonia, abdominal pain, stomatitis, diarrhea, and headache. Nurses should carefully assess for these adverse effects and provide appropriate education regarding their prevention.
Ibrutinib: Pediatric First Approval. [2023]Ibrutinib (IMBRUVICA®), a small molecule inhibitor of Bruton's tyrosine kinase (BTK) developed by Pharmacyclics, Inc. and Janssen Pharmaceutical, is well established as a treatment for B-cell malignancies and is also approved in the USA in adult patients with chronic graft-versus-host disease (cGVHD) and in Japan in adults and adolescents aged ≥ 12 years with cGVHD. Ibrutinib was approved in August 2022 in the USA for use in pediatric patients with cGVHD after failure of one or more lines of systemic therapy and is the first treatment approved for use in this group of patients aged < 12 years (ibrutinib is now indicated for the treatment of adult and pediatric patients aged 1 year and older with cGVHD after failure of one or more lines of systemic therapy). This article summarizes the milestones in the development of ibrutinib leading to this pediatric first approval for the treatment of patients with cGVHD.