Acute Lymphocytic Leukemia, Acute Myelogenous Leukemia, Hodgkin Disease, Myelodysplastic Syndromes, Non-Hodgkin Lymphoma
Conditions
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.
Interventions
PROCEDUREStem cell transplantation
Standard of care
DRUGItacitinib
Itacitinib may be taken without regard to food.
OTHERFunctional 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)
OTHERHuman 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)
Sponsors
Incyte Corporation
American Society of Hematology
National Cancer Institute (NCI)
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pilot Study: 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. | 22 |
| Expansion Phase: 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 | 27 |
| Donors -Donors were consented for the patients enrolled in the Safety Lead-In Phase (planned 3 patients). Donors were consented for a second CD34+ collection to use as a rescue in the case of engraftment failure and for collection of a research blood specimen prior to mobilization. | 6 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Did not continue with treatment due to low donor collection | 2 | 1 | 0 |
| Overall Study | Non-compliance | 0 | 1 | 0 |
| Overall Study | Recipient did not continue with treatment due to low donor cell collection | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Pilot Study: Itacitinib | Total | Donors | Expansion Phase: Itacitinib |
|---|---|---|---|---|
| Age, Continuous | 57.5 years | 58 years | 37.5 years | 61 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 54 Participants | 6 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 49 Participants | 6 Participants | 25 Participants |
| Region of Enrollment United States | 22 participants | 55 participants | 6 participants | 27 participants |
| Sex: Female, Male Female | 10 Participants | 21 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 12 Participants | 34 Participants | 4 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 20 | 8 / 25 | 0 / 0 |
| other Total, other adverse events | 20 / 20 | 26 / 26 | 0 / 0 |
| serious Total, serious adverse events | 14 / 20 | 24 / 26 | 0 / 0 |
Outcome results
Primary
Number of Participants With 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).
Time frame: Through day 100
Population: Donors were not evaluable for this outcome measure. There were 2 participants in the Pilot Study and 2 participants in the Expansion Phase who were not evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pilot Study: Itacitinib | Number of Participants With Grades III-IV Acute GVHD | 0 Participants |
| Expansion Phase: Itacitinib | Number of Participants With Grades III-IV Acute GVHD | 0 Participants |
Primary
Number of Participants With Graft Failure (Pilot Study Only)
Failure to engraft will be defined as failure to achieve absolute neutrophil count \>500 for 3 days by day 35.
Time frame: By day 35
Population: Donors and participants in the Expansion Phase were not evaluable for this outcome measure. There were 2 participants in the Pilot Study who were not evaluable due to not continuing with treatment due to low donor collection.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pilot Study: Itacitinib | Number of Participants With Graft Failure (Pilot Study Only) | 0 Participants |
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). * The cumulative incidence of aGVHD was estimated using Fine-Gray's sub-distribution methods to account for competing risk of death without aGVHD.
Time frame: Day 100
Population: Donors and participants in the Pilot Phase are not evaluable for this outcome measure. There were 2 participants in the Expansion Phase who were not evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Expansion Phase: Itacitinib | Cumulative Incidence of Grades II-IV Acute GVHD (Expansion Phase) | 20 percent |
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. 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
Time frame: Through day 28
Population: Donors were not evaluable for this outcome measure. There were 2 participants in the Pilot Study and 2 participants in the Expansion Phase who were not evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pilot Study: Itacitinib | Number of Participants Who Experience Cytokine Release Syndrome (CRS) | Grade 1 or above | 18 Participants |
| Pilot Study: Itacitinib | Number of Participants Who Experience Cytokine Release Syndrome (CRS) | Grade 2 or above | 5 Participants |
| Expansion Phase: Itacitinib | Number of Participants Who Experience Cytokine Release Syndrome (CRS) | Grade 1 or above | 15 Participants |
| Expansion Phase: Itacitinib | Number of Participants Who Experience Cytokine Release Syndrome (CRS) | Grade 2 or above | 1 Participants |
Secondary
Number of Participants With 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
Time frame: Day 180
Population: Donors were not evaluable for this outcome measure. There were 2 participants in the Pilot Study and 2 participants in the Expansion Phase who were not evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pilot Study: Itacitinib | Number of Participants With Treatment Related Mortality | 0 Participants |
| Expansion Phase: Itacitinib | Number of Participants With Treatment Related Mortality | 0 Participants |