Study of Baricitinib, a JAK1/2 Inhibitor, in Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation
- Conditions
- Chronic Graft-Versus-Host DiseaseChronic Graft vs Host Disease
- Interventions
- Registration Number
- NCT02759731
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
Chronic graft versus host disease (cGVHD) can affect people who had a hematopoietic stem cell transplant using donor cells. It is often fatal. It is usually treated with high doses of steroids. But that helps only about half the people in the long term. Researchers want to see if a drug called baricitinib can help people with cGVHD that has not responded to therapy. The drug inhibits the proteins involved in communication in the immune system. These proteins may play a role in cGVHD and other inflammatory diseases.
Objectives:
To test the safety and effectiveness of baricitinib in people with cGVHD that has not responded to therapy.
Eligibility:
Adults 18 and older with cGVHD that has not responded to therapy.
Design:
Participants will be screened with a medical history, physical exam, and blood and urine tests. They will have lung and heart tests and chest scans.
Baseline visit: Participants will have:
Medical history
Physical exam
Blood tests
Tests for infectious diseases
Skin, eye, and teeth evaluations
Rehabilitation and occupational medicine evaluations
Photos of any lesions
Gynecology evaluation (females)
The study will occur in 28-day cycles. Participants will take the study drug by mouth every day for 3 cycles. Some will take it for 3 or 6 more cycles.
Participants will have a few visits during each cycle. They will repeat some previous tests. They may also have scans and questionnaires.
Participants will have a visit when they stop taking the drug and another 3 months later. They will repeat a few study tests. They will have follow-up calls for 2 years.
- Detailed Description
* Background:
* Chronic graft-versus-host disease (cGVHD) is the leading cause of non-relapse morbidity and mortality in persons after allogeneic hematopoietic stem cell transplantation (SCT).
* Approximately 50% of patients with cGVHD have disease refractory to systemic corticosteroids; currently, there is no standard second-line therapy.
* The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway relays the signaling function of several inflammatory cytokines that have a role in GVHD (interferon (IFN)-gamma, Interleukin-2 (IL-2), Interleukin-6 (IL-6), Interleukin-12 (IL-12)).
* Murine models have demonstrated activity of JAK inhibitors in graft-versus-host disease.
* Baricitinib is a potent and selective inhibitor of Janus kinase 1 (JAK1) and Janus kinase 1 (JAK2) that has demonstrated anti-inflammatory effects and a good safety profile in patients with rheumatoid arthritis but has not been evaluated in GVHD.
* Objectives:
* To determine the safety and tolerability of baricitinib in patients with cGVHD that is refractory to steroids
* To determine the efficacy of baricitinib in patients with cGVHD that is refractory to steroids
* Eligibility:
* Inclusion:
* Age greater than or equal to 18 years
* Moderate or severe cGVHD per NIH consensus criteria
* Karnofsky performance status greater than or equal to 50%
* cGVHD that did not respond to high-dose corticosteroids (prednisone at 1.0 mg/kg/day for at least 1 week or prednisone at 0.5 mg/kg/day or 1 mg/kg every other day for at least 4 weeks), or second-line therapy (any)
* Receiving stable or tapering doses of systemic therapy in the preceding 4 weeks if taking systemic therapy for cGVHD
* Exclusion:
* Neutrophils \<1.0x10\^9/L, platelets \<50X10\^9/L, creatinine greater than or equal to 1.5 times the upper limit of normal or estimated creatinine clearance \<50mL/min/1.73m\^2 (Cockroft-Gault formula), serum aspartate aminotransferase or alanine aminotransferase concentration \>3x upper limit of normal (ULN) or total bilirubin greater than or equal to 1.5x ULN
* Progressive malignancy, uncontrolled infection or any major organ dysfunction as defined by the protocol
* Design:
* This is a Phase 1/2 trial to determine the safety and efficacy of baricitinib in patients with cGVHD that is refractory to steroids.
* Patients will initially be treated with baricitinib at 2mg daily for 12 weeks. If the response at 12 weeks is a complete response (CR) and there has not been a dose-limiting toxicity (DLT), the dose will remain at 2mg daily for an additional 12 weeks, with the primary response assessment at 24 weeks of total treatment. If the response is a partial response (PR) or stable disease, the dose will be increased to 4mg daily for an additional 12 weeks, with the primary response assessment at 24 weeks of total treatment. If there is progression of disease at any time within the first 12 weeks, the dose can be increased to 4mg daily at that time, and patients will continue for a total of 24 weeks of treatment. Patients will have the option to continue baricitinib for an additional 6 months as tolerated if they have stable or responding disease.
* The co-primary endpoint of safety will be determined by rate, severity, and duration of adverse events based on Common Terminology Criteria for Adverse Events (CTCAE) v4 criteria. Assessment for DLTs will occur every 2 weeks during the first 4 weeks of each dose level. Safety monitoring will occur every 4 weeks thereafter.
* The co-primary endpoint of efficacy will be defined as rate of overall response at 24 weeks per National Institutes of Health (NIH) consensus criteria (CR or PR).
* Peripheral blood samples will be collected prior to treatment, at 2 weeks, at 12 weeks and every 12 weeks thereafter to evaluate cytokine and cellular profiles, STAT phosphorylation, candidate chronic GVHD biomarkers. Pharmacokinetic studies will also be performed at each dose level.
* In an initial futility analysis, if 0 of the first 7 patients enrolled in cohort 1 have responded at 12 weeks, then a 2nd cohort of patients will be accrued to start treatment at the higher dose (4mg daily). Otherwise, if 1 or more of the first 7 patients respond in cohort 1, then 21 evaluable patients will be treated in cohort 1. Similarly, if the second cohort is used, and if 0 of the 7 patients enrolled in this second cohort have responded at 12 weeks, then no further patients will be accrued. Otherwise, if 1 or more of the first 7 patients respond in cohort 2, then 21 evaluable patients will be treated in cohort 2.
* A total of 21 evaluable patients will be enrolled in either cohort 1 or 2 as appropriate, in order to have 80% power to detect a response rate consistent with 30% and ruling out 10%, with a one-sided significance level of 0.10 for the cohort. As an early stopping rule for safety, if 2/3 or greater patients at any given dose level experiences a dose limiting toxicity requiring dose reduction or discontinuation, that dose will not be subsequently used, and no further dose escalation will take place.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 24
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Baricitinib Baricitinib Single arm, intra-patient dose escalation. Arm 1 (starting dose) -Baricitinib starting at a dose of 2mg daily for 12 weeks. If the response at 12 weeks is a complete response (CR) and there has not been a dose-limiting toxicity (DLT), the dose will remain at 2mg daily for an additional 12 weeks. Arm 2 (dose escalation) - If the response is a partial response (PR) or stable disease (from cohort 1), the dose will be increased to 4mg daily for an additional 12 weeks. If there has been a DLT within the first 4 weeks will have a dose reduction back to 2mg daily. Each participant is exposed to both dose levels (with the exception of participants who developed toxicity or progressive disease that caused them to discontinue study early before they were able to undergo the per-protocol dose escalation at 12 weeks).
- Primary Outcome Measures
Name Time Method Phase 1: Number of Participants With Dose-Limiting Toxicities (DLT) Starting at each dose level initiation, every 2 weeks up to the first 4 weeks of each dose DLT is defined as any grade ≥3 non-hematologic or grade ≥4 hematologic adverse event, or hemoglobin \<6.5 g/dL, within 4 weeks of starting any dose level (1mg, 2mg, or 4 mg) except those that are clearly and incontrovertibly due to extraneous causes. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe. Grade 4 is life-threatening.
Phase 2: Number of Participants With Any Serious and/or Non-Serious Grades 3, 4, and/or 5 Adverse Events Due to Drug every 4 weeks through study completion (up to 48 weeks) Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe. Grade 4 is life-threatening. And Grade 5 is death related to adverse event.
Phase 2: Overall Response at 24 Weeks 24 weeks Response was assessed by the National Institutes of Health (NIH) chronic graft-versus-host disease (cGVHD) response criteria. Complete Response (CR) is defined as resolution of all manifestations in each organ or site. Partial Response (PR) is defined as improvement at least 1 organ or site without progression in any other organ or site. Lack of Response including unchanged, mixed response, and disease progression. Mixed response is a CR or PR in at least 1 organ accompanied by progression in another organ. Unchanged is outcomes that do not meet the criteria for CR, PR, disease progression, or mixed response. Disease Progression is a change in the manifestations in each organ or site that does not meet the criteria for CR, PR, mixed response, unchanged or lack of response.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States