Clinical trial NCT03755414: Study of Itacitinib for the Prophylaxis of Graft-Versus-Host Disease and Cytokine Release Syndrome After T-cell Replete Haploidentical Peripheral Blood Hematopoietic Cell Transplantation
Official title: A Single-Arm, Open-Label, Pilot Study and Expansion Study of JAK Inhibitor Itacitinib for the Prophylaxis of Graft-Versus-Host Disease and Cytokine Release Syndrome After T-cell Replete Haploidentical Peripheral Blood Hematopoietic Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myelogenous Leukemia
Acute Lymphocytic Leukemia
Myelodysplastic Syndromes
Non-Hodgkin Lymphoma
Hodgkin Disease
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Incyte Corporation
name: American Society of Hematology
name: National Cancer Institute (NCI)
First posted: 2018-11-28
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: In this trial, the investigators will begin to explore the possibility that, as in mice, janus kinase inhibitor 1 (JAK1) inhibition with haploidentical-hematopoietic cell transplantation (HCT) may mitigate graft-versus-host-disease (GVHD) and cytokine release syndrome (CRS) while retaining Graft-versus-Leukemia (GVL) and improving engraftment. The purpose of this pilot study is to determine the safety of itacitinib with haplo-hematopoietic cell transplantation (HCT) measured by the effect on engraftment and grade III-IV GVHD.


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 International Working Group (IWG) Criteria)
  * Acute lymphocytic leukemia (ALL) in complete morphological remission (MRD negative, based on IWG Criteria)
  * Myelodysplastic syndrome with ≤ 5% 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 T Cell-replete peripheral blood haploidentical donor transplantation
* Available human leukocyte antigen (HLA)-haploidentical donor who meets the following criteria:

  * Blood-related family member, including (but not limited to) sibling, offspring, cousin, nephew, or parent. Younger donors should be prioritized.
  * At least 18 years of age
  * HLA-haploidentical donor/recipient match by at least low-resolution typing per institutional standards.
  * In the investigator's opinion, is in general good health, and medically able to tolerate leukapheresis required for harvesting hematopoietic stem cells (HSC).
  * No active hepatitis.
  * Negative for human T-cell lymphotrophic virus (HTLV) and human immunodeficiency virus (HIV).
  * Not pregnant.
  * Safety Lead-In Phase: For the first three patients, the donor 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
  * Aspartate aminotransferase (AST)(SGOT) and alanine aminotransferase (ALT) (SGPT) ≤ 3.0 x institutional upper limit of normal (IULN).
  * Creatinine ≤ 1.5 x IULN OR creatinine clearance ≥ 45 mL/min/1.73 m\^2 by Cockcroft-Gault Formula.
  * Oxygen saturation ≥ 90% on room air.
  * Left ventricular ejection fraction (LVEF) ≥ 40%.
  * Forced expiratory volume (FEV1) and forced vital capacity (FVC) ≥ 40% predicted, diffusing capacity of the lung for carbon monoxide (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 Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable).
* Must be able to receive GVHD prophylaxis with tacrolimus, mycophenolate mofetil, and cyclophosphamide

Exclusion Criteria:

* Must not have undergone a prior allogeneic donor (related, unrelated, or cord) transplant. Prior autologous transplant is not exclusionary.
* Presence of donor-specific antibodies (DSA) with Mean Fluorescence Intensity (MFI) of ≥2000 as assessed by the single antigen bead assay.
* Known HIV or active hepatitis B or C infection.
* Known hypersensitivity to one or more of the study agents, including Ruxolitinib and Itacitinib.
* Must not have myelofibrosis (unless they are enrolled Amendment #5 or later) or other disease known to prolong neutrophil engraftment to \> 35 days after transplant.
* Must not receive antithymocyte globulin as part of pre-transplant conditioning regimens.
* 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.

Additional Inclusion Criteria Under Amendment 5

* Five subjects with myelofibrosis will be enrolled in the expansion phase.
* Three patients whose donors fail to collect the target number of CD34+ cells and the treating physician choses to move forward with the haplo-HCT will be enrolled in the expansion phase.

Primary outcomes:
measure: Number of Participants With Graft Failure (Pilot Study Only)
timeFrame: By day 35
measure: Number of Participants With Grades III-IV Acute GVHD
timeFrame: Through day 100
Secondary outcomes:
measure: Number of Participants Who Experience Cytokine Release Syndrome (CRS)
timeFrame: Through day 28
measure: Number of Participants With Treatment Related Mortality
timeFrame: Day 180
measure: Cumulative Incidence of Grades II-IV Acute GVHD (Expansion Phase)
timeFrame: Day 100
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: Ramzi Abboud, M.D.
role: PRINCIPAL_INVESTIGATOR
References: