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

Phase 1

Completed

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

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

Registration Number: NCT03755414

Lead Sponsor: Washington University School of Medicine

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 55

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Pilot Study: Itacitinib	Stem cell transplantation	* 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.
Expansion Phase: Itacitinib	Stem cell transplantation	* 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
Pilot Study: Itacitinib	Itacitinib	* 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.
Pilot Study: Itacitinib	Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT)	* 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.
Pilot Study: Itacitinib	Human Activity Profile	* 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.
Expansion Phase: Itacitinib	Itacitinib	* 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
Expansion Phase: Itacitinib	Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT)	* 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
Expansion Phase: Itacitinib	Human Activity Profile	* 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

Primary Outcome Measures

Name	Time	Method
Number of Participants With Graft Failure (Pilot Study Only)	By day 35	Failure to engraft will be defined as failure to achieve absolute neutrophil count \>500 for 3 days by day 35.
Number of Participants With Grades III-IV Acute GVHD	Through day 100	-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

Name	Time	Method
Number of Participants Who Experience Cytokine Release Syndrome (CRS)	Through day 28	* The number of participants who experience CRS will be summarized by count of participants who experience Grade 1, 2, 3, 4, \& 5 CRS. The worst grade experienced by participant will be noted. * 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
Number of Participants With Treatment Related Mortality	Day 180	-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)	Day 100	* 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). * The cumulative incidence of aGVHD was estimated using Fine-Gray's sub-distribution methods to account for competing risk of death without aGVHD.