Front Line Ibrutinib Without Corticosteroids for Newly Diagnosed Chronic Graft-versus-Host Disease
- Conditions
- Chronic GVHD
- Interventions
- Diagnostic Test: ECGDiagnostic Test: PFT'sDiagnostic Test: CTDrug: Steroid pulse (prednisone)Drug: BeclomethasoneOther: FilgrastimOther: PegfilgrastimOther: ErythropoietinOther: TransfusionsProcedure: Oral/Skin biopsy
- Registration Number
- NCT04294641
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
- Chronic Graft Versus Host Disease (cGVHD) can occur after a person has had a stem cell or bone marrow transplant. In cGVHD, the donor cells attack the recipient's body. Researchers want to see if a drug called ibrutinib can block one of the proteins that lead to the immune reaction that causes cGVHD.
Objective:
- To see if ibrutinib as a first-line treatment can help people with newly diagnosed cGVHD.
Eligibility:
- People age 18 and older with newly diagnosed moderate or severe cGVHD
Design:
* Participants will be screened with:
* Medical and medicine histories
* Physical exam and vital signs
* Electrocardiograms (to measure heart function)
* Assessment of their ability to perform daily activities
* Blood and urine tests
* Assessment of their general well-being.
* Participants will visit the Clinical Center every 2 weeks for the first 2 months. Then they will visit every 4 weeks.
* Participants will take ibrutinib by mouth once every day of every cycle. One cycle is 28 days. Treatment will last up to 2 years. Participants will keep a medicine diary.
* Participants will take tests to measure lung function. They may have computed tomography scans of their chest. They will complete questionnaires about their symptoms and how cGVHD is affecting their body and quality of life. They will repeat the screening tests.
* Participants may have optional blood tests and/or skin biopsies to better understand the drugs effect on the body.
* Participants will be contacted by phone 30 days after treatment ends. They will also be contacted once a year for 2 years to discuss how they are feeling and if they have taken any other medicines to treat cGVHD.
- Detailed Description
Background:
* Chronic graft-versus-host disease (GvHD) is the leading cause of late morbidity and non-relapse mortality following allogeneic hematopoietic stem cell transplantation (alloHSCT), occurring in 40-60% long-term survivors.
* Chronic GvHD occurs due to the dysfunctional peripheral tolerance during post-transplant hematopoietic reconstitution that allows the development and persistence of alloreactive donor-derived T and B cells.
* Prednisone is the front-line therapy; however, about 50% of participants have steroid-refractory disease and there is no standard second-line therapy.
* The most attractive approach for controlling chronic GvHD would be early therapy intervention which could prevent the most severe and irreversible clinical manifestations.
* Anti-B-cell therapy delivered early in chronic GvHD could be effective and steroid-sparing.
* Ibrutinib, reversible small molecule inhibitor of Brutons tyrosine kinase, has been shown to be well-tolerated and effective in phase 1b/2 trial for steroid refractory chronic GvHD.
Objective:
-To evaluate efficacy of ibrutinib as a first-line treatment for persons with newly diagnosed chronic GvHD by measuring the overall response rate (complete response \[CR\] + partial response \[PR\]) at 6 months, according to the 2014 National Institutes of Health (NIH) Consensus Criteria
Eligibility:
* Newly diagnosed, moderate or severe chronic GvHD according to the 2014 NIH Consensus Criteria, requiring systemic immunosuppression
* Age greater than or equal to 18 years old
* Karnofsky performance status greater than or equal to 60%
* History of prior alloHSCT; any donors, conditioning regimens and graft sources are allowed
* Adequate cardiac, hepatic and other organ function
* Adequate laboratory parameters
Design:
* Multi-center, non-randomized, phase II study
* Two-stage design will be used to determine the overall response rate (CR + PR) at 6 months
* Continuous daily dose of ibrutinib 420 mg by mouth, with the potential for dose reductions to 280 mg and 140 mg
* The accrual ceiling will be set at 40 participants, allowing for a total of up to 28 evaluable subjects.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 10
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Ibrutinib Without Corticosteroids Ibrutinib Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids ECG Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids PFT's Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids CT Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Steroid pulse (prednisone) Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Voriconazole Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Posaconazole Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Azithromycin Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Montelukast Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Budesonide Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Beclomethasone Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Filgrastim Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Pegfilgrastim Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Erythropoietin Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Transfusions Determine response rate via continuous daily dose by mouth to determine efficacy Ibrutinib Without Corticosteroids Oral/Skin biopsy Determine response rate via continuous daily dose by mouth to determine efficacy
- Primary Outcome Measures
Name Time Method Fraction of Participants With an Overall Response Rate (Complete Response [CR] + Partial Response [PR]) Reported With an 80% Confidence Interval at 6 Months At 6 months To evaluate the efficacy of Ibrutinib as a first-line treatment for persons with newly diagnosed chronic graft-versus-host disease (GvHD) overall response rate was measured using the 2014 National Institutes of Health (NIH) consensus criteria and reported with an 80% confidence interval. CR is defined as complete resolution in all of signs and symptoms at all affected organs or tissues. PR is defined as improvement in ≥1 organ or tissue with no progression in any other affected organ or tissue.
Fraction of Participants With an Overall Response Rate (Complete Response [CR] + Partial Response [PR]) Reported With an 95% Confidence Interval at 6 Months At 6 months To evaluate the efficacy of Ibrutinib as a first-line treatment for persons with newly diagnosed chronic graft-versus-host disease (GvHD) overall response rate was measured using the 2014 National Institutes of Health (NIH) consensus criteria and reported with a 95% confidence interval. CR is defined as complete resolution in all of signs and symptoms at all affected organs or tissues. PR is defined as improvement in ≥1 organ or tissue with no progression in any other affected organ or tissue.
- Secondary Outcome Measures
Name Time Method Fraction of Grade 3 and Grade 4 Serious and/or Non-serious Adverse Events in Participants With Newly Diagnosed Chronic Graft-versus-host Disease (GvHD) Adverse events are captured from the first study intervention, Study Day 1 of Cycle 1 through 30 days after the participant received the last study drug administration. Safety of the agent will be determined by the fraction of grade of 3 and 4 serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 3 is severe, and Grade 4 is life-threatening.
Failure-free Survival (FFS) Participants were followed from enrollment without death, relapse or new GVHD treatment up to 14 months Time to event endpoint failure free survival will be determined using a Kaplan-Meier curve and confidence intervals is calculated using the Brookmeyer-Crowley method. Failure-free survival (FFS) is defined as survival (from enrollment) without death, relapse of the underlying malignancy, or the addition of a new systemic chronic graft-versus-host-disease (GVHD) treatment.
Fraction of Participants Alive at 24 Months Follow-up Post-treatment 24 months Survival will be determined using a Kaplan-Meier curve at 24 months.
Trial Locations
- Locations (2)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States
Washington University, School of Medicine
🇺🇸Saint Louis, Missouri, United States