Baricitinib for the Prophylaxis of Graft-Versus-Host Disease After Peripheral Blood Hematopoietic Cell Transplantation
Study Details
Study Description
Brief Summary
In this trial, the investigators will begin to explore the possibility that, as in mice, JAK1/2 inhibition with hematopoietic cell transplantation (HCT) may mitigate graft-versus-host-disease (GVHD) while retaining engraftment and Graft-versus-Leukemia (GVL). Both preclinical and clinical data suggest that inhibition of IFNy and IL-6, directly and using downstream JAK Inhibitors, may be an effective strategy to decrease toxicities and improve disease control for patients undergoing Allogeneic HSCT. Baricitinib, as a JAK1/2 inhibitor, has shown superiority to other JAK inhibitors in preclinical GVHD models. The purpose of this phase I clinical trial is to determine the safety of baricitinib with HSCT measured by the effect on engraftment and grade III-IV acute graft-versus-host-disease (aGVHD).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Baricitinib 2 mg Dose Level On Day 0 the allograft will be infused per standard institutional practice Baricitinib will be administered PO at a starting dose of 2 mg daily from Day -3 to Day 100 After Day 100, for patients already dose reduced to 2 mg daily, reduce baricitinib to 2 mg every other day for one month or 1 mg daily for one month (depending on drug supply) then discontinue. |
Drug: Baricitinib
Baricitinib may be taken without regard to food. It should be taken at the same time every day.
Other Names:
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| Experimental: Baricitinib 4 mg Dose Level On Day 0 the allograft will be infused per standard institutional practice Baricitinib will be administered PO at a starting dose of 4 mg daily from Day -3 to Day 100 After Day 100, for patients at a dose of 4 mg daily, reduce baricitinib to 2 mg daily for one month, then every other day for one month or 1 mg daily for one month (depending on drug supply) then discontinue. |
Drug: Baricitinib
Baricitinib may be taken without regard to food. It should be taken at the same time every day.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Cumulative incidence of graft failure [28 days post transplant]
-Failure to engraft will be defined as failure to achieve absolute neutrophil count > 500 for 3 days by Day 28.
- Cumulative incidence of grade III-IV acute GVHD [Day 100]
-Acute GVHD will be assessed using MAGIC criteria
Secondary Outcome Measures
- Treatment related mortality [Day 180]
-Death that results from a transplant procedure-related complication (e.g. infection, organ failure, hemorrhage, GVHD) rather than from relapse of the underlying disease or an unrelated cause.
Eligibility Criteria
Criteria
Inclusion Criteria:
Patients must meet the following criteria within 30 days prior to Day 0 unless otherwise noted.
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Diagnosis of a hematological malignancy listed below:
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Acute myelogenous leukemia (AML) in complete morphological remission (based on IWG Criteria).
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Acute lymphocytic leukemia (ALL) in complete morphological remission (MRD negative, based on IWG Criteria).
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Myelodysplastic syndrome with less than 10% blasts in bone marrow.
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Non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) in 2nd or greater complete or partial remission.
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Planned treatment is myeloablative or reduced intensity conditioning followed by peripheral blood HLA matched donor transplantation
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Available HLA-identical donor who meets the following criteria:
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At least 18 years of age.
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HLA-identical donor/recipient match by high-resolution typing per institutional standards.
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In the investigator's opinion, is in general good health, and medically able to tolerate leukapheresis required for harvesting HSC.
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No active hepatitis.
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Negative for HTLV and HIV.
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Not pregnant.
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Donor selection will be in compliance with institutional standards
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Safety Lead-In Phase: For the first three patients at each dose level, related donors must consent to a second product collection should it prove necessary.
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Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
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Adequate organ function as defined below:
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Total bilirubin must be within normal range at baseline.
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AST (SGOT) and ALT (SGPT) ≤ 3.0 x IULN.
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Estimated creatinine clearance ≥ 60 mL/min/1.73 m2 by Cockcroft-Gault Formula.
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Oxygen saturation ≥ 90% on room air.
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LVEF ≥ 40%.
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FEV1 and FVC ≥ 40% predicted, DLCOc ≥ 40% predicted. If DLCO is < 40%, patients will still be considered eligible if deemed safe after a pulmonary evaluation.
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At least 18 years of age at the time of study registration
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Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
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Must be able to receive GVHD prophylaxis with tacrolimus, mini-methotrexate with or without ATG or post transplant Cy with MMF and tacrolimus as outlined in the protocol
Exclusion Criteria:
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Must not have undergone a prior allogeneic donor (related, unrelated, or cord) transplant. Prior autologous transplant is not exclusionary.
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Known HIV or active hepatitis B or C infection.
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Known latent tuberculosis infection, or at high risk for latent TB infection, or a positive t-spot tuberculosis test
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Known hypersensitivity to one or more of the study agents, including baricitinib.
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Must not have myelofibrosis or other disease known to prolong neutrophil engraftment to > 35 days after transplant.
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Currently receiving or has received any investigational drugs within the 14 days prior to the first dose of study drug (Day -3).
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Pregnant and/or breastfeeding.
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Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, autoimmune disease, symptomatic congestive heart failure, unstable angina pectoris, unstable cardiac arrhythmias, or psychiatric illness/social situations that would limit compliance with study requirements.
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Immunosuppressive doses of steroids. Subjects with steroids for adrenal insufficiency will not be excluded.
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History of unprovoked thrombosis or known thrombophilia. Provoked and/or superficial DVTs are eligible provided they are treated and resolved at the time of screening.
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Recent (less than 1 year from screening) myocardial infarction or embolic stroke
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
Sponsors and Collaborators
- Washington University School of Medicine
Investigators
- Principal Investigator: Mark A Schroeder, M.D., Washington University School of Medicine
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 201911012