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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia, Myelodysplastic Syndromes, Non-Hodgkin Lymphoma, Hodgkin Disease

Intervention / Treatment
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* Procedure: Stem cell transplantation
* Drug: Itacitinib
* Other: Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT)
* Other: Human Activity Profile


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pilot Study: Itacitinib<br>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. | Procedure: Stem cell transplantation<br>* Standard of care<br>Drug: Itacitinib<br>* Itacitinib may be taken without regard to food.<br>Other: Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT)<br>* 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)<br>Other: Human Activity Profile<br>* 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)<br>|
| Experimental: Expansion Phase: Itacitinib<br>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. | Procedure: Stem cell transplantation<br>* Standard of care<br>Drug: Itacitinib<br>* Itacitinib may be taken without regard to food.<br>Other: Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT)<br>* 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)<br>Other: Human Activity Profile<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of graft failure (pilot study only) |  | 35 days post haplo-HCT | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 | 
| 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 |