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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

Primary Purpose

Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia, Myelodysplastic Syndromes

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Stem cell transplantation
Itacitinib
Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT)
Human Activity Profile
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myelogenous Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Washington University School of MedicineRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Pilot Study: Itacitinib

Expansion Phase: Itacitinib

Arm Description

Will undergo institutionally standard myeloablative or reduced intensity chemotherapy or chemoradiotherapy Stem cell transplantation on Day 0 Itacitinib 200 mg/day from Day -3 to Day 100. After Day 100, for patients at a dose of 200 mg daily, reduce to 100 mg daily for 1 month, then every other day for one month, then discontinue OR after day 100, for patients already dose reduced to 100 mg daily, reduce to 100 mg every other day then discontinue OR after day 100, for patients on study drug hold, discontinue permanently To address concerns of engraftment failure using itacitinib throughout the transplant period, for the first three patients the investigators will consent the donor for a second CD34+ collection to use as a rescue in the case of engraftment failure.

Will undergo institutionally standard myeloablative or reduced intensity chemotherapy or chemoradiotherapy Stem cell transplantation on Day 0 Itacitinib 200 mg/day from Day -3 to Day 180. After Day 180, for patients at a dose of 200 mg daily, reduce to 100 mg daily for 1 month, then every other day for one month, then discontinue OR after day 180, for patients already dose reduced to 100 mg daily, reduce to 100 mg every other day then discontinue OR after day 180, for patients on study drug hold, discontinue permanently To address concerns of engraftment failure using itacitinib throughout the transplant period, for the first three patients the investigators will consent the donor for a second CD34+ collection to use as a rescue in the case of engraftment failure.

Outcomes

Primary Outcome Measures

Cumulative incidence of graft failure (pilot study only)
Cumulative incidence of grades III-IV acute GVHD
-Incidence of acute grade III-IV GVHD will be assessed using Mount Sinai Acute GvHD International Consortium (MAGIC) criteria. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).

Secondary Outcome Measures

Number of participants who experience cytokine release syndrome (CRS)
The number of participants who experience CRS will be summarized by count of participants who experience Grade 1, 2, 3, 4, & 5 CRS. Grade 1: symptoms not life threatening & require symptomatic treatment alone, includes fever, nausea, fatigue, malaise Grade 2: symptoms require/respond to limited intervention - oxygen (O2) <40%, <=3 liters (L) nasal cannula or hypotension responsive to fluids or low dose of 1 vasopressor or grade 2 renal or hepatic toxicity Grade 3: symptoms require/respond to aggressive intervention - O2 >=40%, >3L nasal cannula or hypotension requiring high dose or multiple vasopressors or grade 3 renal toxicity or grade 4 transaminitis, new onset altered mental status, new cardiomyopathy without wall motion abnormality Grade 4: life-threatening symptoms - requirement for ventilator support or grade 4 rental toxicity (excluding transaminitis) Grade 5: death
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
Cumulative incidence of grades II-IV acute GVHD (expansion phase)
-Incidence of acute grade II-IV GVHD will be assessed using Mount Sinai Acute GvHD International Consortium (MAGIC) criteria. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).

Full Information

First Posted
November 20, 2018
Last Updated
June 21, 2023
Sponsor
Washington University School of Medicine
Collaborators
Incyte Corporation, American Society of Hematology
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1. Study Identification

Unique Protocol Identification Number
NCT03755414
Brief Title
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

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 4, 2019 (Actual)
Primary Completion Date
February 22, 2024 (Anticipated)
Study Completion Date
May 13, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
Incyte Corporation, American Society of Hematology

4. Oversight

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.
Yes
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia, Myelodysplastic Syndromes, Non-Hodgkin Lymphoma, Hodgkin Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
55 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Pilot Study: Itacitinib
Arm Type
Experimental
Arm Description
Will undergo institutionally standard myeloablative or reduced intensity chemotherapy or chemoradiotherapy Stem cell transplantation on Day 0 Itacitinib 200 mg/day from Day -3 to Day 100. After Day 100, for patients at a dose of 200 mg daily, reduce to 100 mg daily for 1 month, then every other day for one month, then discontinue OR after day 100, for patients already dose reduced to 100 mg daily, reduce to 100 mg every other day then discontinue OR after day 100, for patients on study drug hold, discontinue permanently To address concerns of engraftment failure using itacitinib throughout the transplant period, for the first three patients the investigators will consent the donor for a second CD34+ collection to use as a rescue in the case of engraftment failure.
Arm Title
Expansion Phase: Itacitinib
Arm Type
Experimental
Arm Description
Will undergo institutionally standard myeloablative or reduced intensity chemotherapy or chemoradiotherapy Stem cell transplantation on Day 0 Itacitinib 200 mg/day from Day -3 to Day 180. After Day 180, for patients at a dose of 200 mg daily, reduce to 100 mg daily for 1 month, then every other day for one month, then discontinue OR after day 180, for patients already dose reduced to 100 mg daily, reduce to 100 mg every other day then discontinue OR after day 180, for patients on study drug hold, discontinue permanently To address concerns of engraftment failure using itacitinib throughout the transplant period, for the first three patients the investigators will consent the donor for a second CD34+ collection to use as a rescue in the case of engraftment failure.
Intervention Type
Procedure
Intervention Name(s)
Stem cell transplantation
Intervention Description
Standard of care
Intervention Type
Drug
Intervention Name(s)
Itacitinib
Intervention Description
Itacitinib may be taken without regard to food.
Intervention Type
Other
Intervention Name(s)
Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT)
Intervention Description
Screening, day 14, day 28, day 42, day 74, day 100, taper period, and follow-up (pilot study) Screening, day 14, day 28, day 42, day 74, day 100, day 180, taper period, and follow-up period (expansion study)
Intervention Type
Other
Intervention Name(s)
Human Activity Profile
Intervention Description
Screening, day 14, day 28, day 42, day 74, day 100, taper period, and follow-up (pilot study) Screening, day 14, day 28, day 42, day 60, day 74, day 100, day 180, taper period, and follow-up period (expansion study)
Primary Outcome Measure Information:
Title
Cumulative incidence of graft failure (pilot study only)
Time Frame
35 days post haplo-HCT
Title
Cumulative incidence of grades III-IV acute GVHD
Description
-Incidence of acute grade III-IV GVHD will be assessed using Mount Sinai Acute GvHD International Consortium (MAGIC) criteria. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).
Time Frame
Day 100
Secondary Outcome Measure Information:
Title
Number of participants who experience cytokine release syndrome (CRS)
Description
The number of participants who experience CRS will be summarized by count of participants who experience Grade 1, 2, 3, 4, & 5 CRS. Grade 1: symptoms not life threatening & require symptomatic treatment alone, includes fever, nausea, fatigue, malaise Grade 2: symptoms require/respond to limited intervention - oxygen (O2) <40%, <=3 liters (L) nasal cannula or hypotension responsive to fluids or low dose of 1 vasopressor or grade 2 renal or hepatic toxicity Grade 3: symptoms require/respond to aggressive intervention - O2 >=40%, >3L nasal cannula or hypotension requiring high dose or multiple vasopressors or grade 3 renal toxicity or grade 4 transaminitis, new onset altered mental status, new cardiomyopathy without wall motion abnormality Grade 4: life-threatening symptoms - requirement for ventilator support or grade 4 rental toxicity (excluding transaminitis) Grade 5: death
Time Frame
Through Day 8 (approximately 1 week post transplant)
Title
Treatment related mortality
Description
-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
Time Frame
Day 180
Title
Cumulative incidence of grades II-IV acute GVHD (expansion phase)
Description
-Incidence of acute grade II-IV GVHD will be assessed using Mount Sinai Acute GvHD International Consortium (MAGIC) criteria. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).
Time Frame
Day 100

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ramzi Abboud, M.D.
Phone
314-454-8304
Email
rabboud@wustl.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ramzi Abboud, M.D.
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ramzi Abboud, M.D.
Phone
314-454-8304
Email
rabboud@wustl.edu
First Name & Middle Initial & Last Name & Degree
Ramzi Abboud, M.D.
First Name & Middle Initial & Last Name & Degree
Mark A Schroeder, M.D.
First Name & Middle Initial & Last Name & Degree
John F DiPersio, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Peter Westervelt, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Camille Abboud, M.D.
First Name & Middle Initial & Last Name & Degree
Amanda Cashen, M.D.
First Name & Middle Initial & Last Name & Degree
Keith Stockerl-Goldstein, M.D.
First Name & Middle Initial & Last Name & Degree
Ravi Vij, M.D.
First Name & Middle Initial & Last Name & Degree
Geoffrey Uy, M.D.
First Name & Middle Initial & Last Name & Degree
Mathew Walter, M.D.
First Name & Middle Initial & Last Name & Degree
Todd Fehniger, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Armin Ghobadi, M.D.
First Name & Middle Initial & Last Name & Degree
Meagan Jacoby, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Iskra Pusic, M.D.
First Name & Middle Initial & Last Name & Degree
Lukas Wartman, M.D.
First Name & Middle Initial & Last Name & Degree
John Welch, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Tanya Wildes, M.D.
First Name & Middle Initial & Last Name & Degree
Terrence Wong, M.D., Ph.D.
First Name & Middle Initial & Last Name & Degree
Francesca Ferraro, M.D., Ph.D.

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). The study protocol will also be made available. Data will be shared with investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary"), for the purpose of achieving their approved aims. Patient who opt out of data sharing will not be included.
IPD Sharing Time Frame
Data will be available beginning 9 months and ending 36 months following article publication
Links:
URL
http://www.siteman.wustl.edu
Description
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Learn more about this trial

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

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