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

Myelodysplastic Syndromes Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03755414
• Other study ID #: 201903114
• Secondary ID: K12CA167540
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: September 4, 2019
• Est. completion date: September 5, 2024

Study information

• Verified date: March 2024
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 55
• Est. completion date: September 5, 2024
• Est. primary completion date: June 17, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphocytic Leukemia
• Acute Myelogenous Leukemia
• Cytokine Release Syndrome
• Graft vs Host Disease
• Hodgkin Disease
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Non-Hodgkin Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Syndrome

Intervention

Procedure:
• Stem cell transplantation
Standard of care

Drug:
• Itacitinib
Itacitinib may be taken without regard to food.

Other:
• Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT)
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)
• Human Activity Profile
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)

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (4)

Lead Sponsor	Collaborator
Washington University School of Medicine	American Society of Hematology, Incyte Corporation, National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cumulative incidence of graft failure (pilot study only)		35 days post haplo-HCT
Primary	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).	Day 100
Secondary	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	Through Day 8 (approximately 1 week post transplant)
Secondary	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
Secondary	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).	Day 100

External Links

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