Ruxolitinib for the Prophylaxis of Graft-Versus-Host Disease and Cytokine Release Syndrome After T-cell Replete Haploidentical Peripheral Blood Hematopoietic Cell Transplantation

An Open-Label Phase I Study With an Expansion Cohort of JAK Inhibitor Ruxolitinib for the Prophylaxis of Graft-Versus-Host Disease and Cytokine Release Syndrome After T-cell Replete Haploidentical Peripheral Blood Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (HCT) is one of the only curative intent therapies available for hematologic malignancies. HLA-matched sibling donors have historically offered the best clinical results but are unavailable for the majority of patients, while most patients do have readily available haploidentical donors. One of the risks of a haploidentical HCT is graft vs. host disease (GVHD), but it is difficult to reduce the incidence of GVHD without compromising the graft vs. leukemia (GVL) effect.

The hypothesis of this study is that JAK inhibition with haploidentical HCT may mitigate GVHD and cytokine release syndrome while retaining the GVL effect and improving engraftment.

Study Overview

• Status: Not yet recruiting
• Conditions: Graft Versus Host Disease; Graft Vs Host Disease; Graft-versus-host-disease
• Intervention / Treatment: Drug: Ruxolitinib

• Study Type: Interventional
• Enrollment (Estimated): 49
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ramzi Abboud, M.D.; Phone Number: 314-454-8304; Email: rabboud@wustl.edu

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
      • Sub-Investigator: Zachary Crees, M.D.
      • Contact: Ramzi Abboud, M.D.; Phone Number: 314-454-8304; Email: rabboud@wustl.edu
      • Principal Investigator: Ramzi Abboud, M.D.
      • Sub-Investigator: Geoffrey Uy, M.D.
      • Sub-Investigator: Armin Ghobadi, M.D.
      • Sub-Investigator: Feng Gao, Ph.D.
      • Sub-Investigator: John Dipersio, M.D., Ph.D.
      • Sub-Investigator: Camille Abboud, M.D.
      • Sub-Investigator: Amanda Cashen, M.D.
      • Sub-Investigator: Keith Stockerl-Goldstein, M.D.
      • Sub-Investigator: Ravi Vij, M.D.
      • Sub-Investigator: Todd Fehniger, M.D., Ph.D.
      • Sub-Investigator: Meagan Jacoby, M.D., Ph.D.
      • Sub-Investigator: Iskra Pusic, M.D.
      • Sub-Investigator: Mark Schroeder, M.D.
      • Sub-Investigator: Brad Kahl, M.D.
      • Sub-Investigator: Matthew Walter, M.D.
      • Sub-Investigator: Kelly Bolton, M.D.
      • Sub-Investigator: Matt Christopher, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients must meet the following criteria within 30 days prior to Day -3 unless otherwise noted.

• Diagnosis of one of the hematological malignancies listed below:

  • Acute myelogenous leukemia (AML) in complete morphological remission, complete remission with incomplete hematologic recovery, and complete remission with partial hematologic recovery (based on ELN Criteria47).
  • Acute lymphocytic leukemia (ALL) in complete morphological remission (MRD negative by flow cytometry with sensitivity to ≤ 10-4).
  • Myelodysplastic syndrome with ≤ 10% blasts in bone marrow.
  • Non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HD) in second or greater complete or partial remission.
  • Myelofibrosis with ≤ 10% blasts in bone marrow. Up to five patients with myelofibrosis will be permitted in the expansion phase ONLY.
• Planned treatment is T cell-replete peripheral blood haploidentical donor transplantation.

• Available 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.
  • No active hepatitis.
  • Negative for HTLV and HIV.
  • Not pregnant.
  • Donor selection will be in compliance with FDA guidelines as provided in 21 CFR 1271 for donor eligibility https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM091345.pdf
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

• Adequate organ function as defined below:

  • Total bilirubin ≤ 1.5 x IULN.
  • AST (SGOT) and ALT (SGPT) ≤ 3.0 x IULN.
  • Creatinine ≤ 1.5 x IULN OR creatinine clearance ≥ 45 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.
• Able to receive GVHD prophylaxis with tacrolimus, mycophenolate mofetil, and cyclophosphamide.
• At least 18 years of age at the time of study registration
• The effects of ruxolitinib on the developing human fetus are unknown. Additionally, tacrolimus may increase risk of hypertension, preeclampsia, preterm birth, and low birth weight; and mycophenolate mofetil is considered to be teratogenic. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of the study.
• Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• Prior allogeneic transplant (regardless of whether donor was related, unrelated, or cord). 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 current and/or history of active tuberculosis.
• Known hypersensitivity to one or more of the study agents.
• Planning to receive antithymocyte globulin as part of the pre-transplant conditioning regimen.
• 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. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, autoimmune disease, symptomatic congestive heart failure, unstable angina pectoris, or unstable cardiac arrhythmias.
• Immunosuppressive doses of steroids. Subjects with steroids for adrenal insufficiency will not be excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I: Ruxolitinib; Ruxolitinib at 5 mg twice per day (BID) beginning on Day -3 and continuing until Day 180 followed by a taper (duration of taper depends on dose of ruxolitinib at Day 180). Once a patient's counts have reached ANC > 1.5 K/cumm, hemoglobin > 9.0 g/dL, and platelets > 50 K/cumm, ruxolitinib dosing will escalate to 10 mg BID.; Ruxolitinib starting dose for patients receiving fluconazole will be 5 mg QD. Patients who remain on fluconazole and meet the target recovery criteria below can increase ruxolitinib dosing to 5 mg BID and subsequently 10 mg BID.	Drug: Ruxolitinib; Ruxolitinib is provided by Incyte Corporation.; Other Names: Jakafi
Experimental: Expansion Phase: Ruxolitinib; Ruxolitinib at 5 mg twice per day (BID) beginning on Day -3 and continuing until Day 180 followed by a taper (duration of taper depends on dose of ruxolitinib at Day 180). Once a patient's counts have reached ANC > 1.5 K/cumm, hemoglobin > 9.0 g/dL, and platelets > 50 K/cumm, ruxolitinib dosing will escalate to 10 mg BID.; Ruxolitinib starting dose for patients receiving fluconazole will be 5 mg QD. Patients who remain on fluconazole and meet the target recovery criteria below can increase ruxolitinib dosing to 5 mg BID and subsequently 10 mg BID.	Drug: Ruxolitinib; Ruxolitinib is provided by Incyte Corporation.; Other Names: Jakafi

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Cumulative incidence of grades III-IV acute GVHD by MAGIC criteria	Day 100
Cumulative incidence of graft failure (Phase I only)	Day 35
Number of patients who experience CRS	Through day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of grades II-IV acute GVHD by MAGIC criteria		Day 100
Treatment-related mortality	Defined as death resulting from a transplant procedure-related complication rather than from relapse of the underlying disease or an unrelated cause	Day 180
Feasibility of regimen (Phase I only)	Defined as at least 80% of patients successfully taking at least 80% of the ruxolitinib dose	From day -3 to day 30

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Incyte Corporation
• Investigators: Principal Investigator: Ramzi Abboud, M.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): April 30, 2024
• Primary Completion (Estimated): August 9, 2026
• Study Completion (Estimated): November 11, 2026

Study Registration Dates

• First Submitted: August 18, 2023
• First Submitted That Met QC Criteria: August 18, 2023
• First Posted (Actual): August 24, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Haploidentical; GVHD; CRS
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Graft vs Host Disease; Cytokine Release Syndrome
• Other Study ID Numbers: 202401211

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No