Baricitinib for the Prophylaxis of Graft-Versus-Host Disease After Peripheral Blood Hematopoietic Cell Transplantation

Study Overview
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Brief Summary
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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).

Official Title
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A Single-Arm, Open-Label Phase I Clinical Trial of a JAK Inhibitor, Baricitinib, for the Prophylaxis of Graft-Versus-Host Disease After Peripheral Blood Hematopoietic Cell Transplantation

Conditions
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Graft-versus-host-disease, Graft Vs Host Disease

Intervention / Treatment
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* Drug: Baricitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet the following criteria within 30 days prior to Day 0 unless otherwise noted. Diagnosis of a hematological malignancy listed below: Acute myelogenous leukemia (AML) in complete morphological remission (based on IWG Criteria). Acute lymphocytic leukemia (ALL) in complete morphological remission (MRD negative, based on IWG Criteria). Myelodysplastic syndrome with less than 10% blasts in bone marrow. Non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) in 2nd or greater complete or partial remission. Planned treatment is myeloablative or reduced intensity conditioning followed by peripheral blood HLA matched donor transplantation Available HLA-identical donor who meets the following criteria: At least 18 years of age. HLA-identical donor/recipient match by high-resolution typing per institutional standards. In the investigator's opinion, is in general good health, and medically able to tolerate leukapheresis required for harvesting HSC. No active hepatitis. Negative for HTLV and HIV. Not pregnant. Donor selection will be in compliance with institutional standards 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. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Adequate organ function as defined below: Total bilirubin must be within normal range at baseline. AST (SGOT) and ALT (SGPT) ≤ 3.0 x IULN. Estimated creatinine clearance ≥ 60 mL/min/1.73 m2 by Cockcroft-Gault Formula. Oxygen saturation ≥ 90% on room air. LVEF ≥ 40%. 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. At least 18 years of age at the time of study registration Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). 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: Must not have undergone a prior allogeneic donor (related, unrelated, or cord) transplant. Prior autologous transplant is not exclusionary. Known HIV or active hepatitis B or C infection. Known latent tuberculosis infection, or at high risk for latent TB infection, or a positive t-spot tuberculosis test Known hypersensitivity to one or more of the study agents, including baricitinib. Must not have myelofibrosis or other disease known to prolong neutrophil engraftment to > 35 days after transplant. Currently receiving or has received any investigational drugs within the 14 days prior to the first dose of study drug (Day -3). Pregnant and/or breastfeeding. 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. Immunosuppressive doses of steroids. Subjects with steroids for adrenal insufficiency will not be excluded. 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. Recent (less than 1 year from screening) myocardial infarction or embolic stroke

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: If all 3 patients in the safety lead-in for the 2 mg dose level achieve engraftment, 9 additional patients will be enrolled at that dose level. If all 3 patients in the safety lead-in for the 4 mg dose level achieve engraftment, 9 additional patients will be enrolled at that dose level.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baricitinib 2 mg Dose Level<br>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<br>* Baricitinib may be taken without regard to food. It should be taken at the same time every day.<br>* Other names: Olumiant;|
| Experimental: Baricitinib 4 mg Dose Level<br>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<br>* Baricitinib may be taken without regard to food. It should be taken at the same time every day.<br>* Other names: Olumiant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of graft failure | -Failure to engraft will be defined as failure to achieve absolute neutrophil count > 500 for 3 days by Day 28. | 28 days post transplant | 
| Cumulative incidence of grade III-IV acute GVHD | -Acute GVHD will be assessed using MAGIC criteria | Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related mortality | -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. | Day 180 |