Clinical trial NCT04131738: Baricitinib for the Prophylaxis of Graft-Versus-Host Disease After Peripheral Blood Hematopoietic Cell Transplantation
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Graft-versus-host-disease
Graft Vs Host Disease
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2019-10-18
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: Cumulative incidence of graft failure
timeFrame: 28 days post transplant
measure: Cumulative incidence of grade III-IV acute GVHD
timeFrame: Day 100
Secondary outcomes:
measure: Treatment related mortality
timeFrame: Day 180
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Mark A Schroeder, M.D.
role: PRINCIPAL_INVESTIGATOR
References: