Adding Itacitinib to Cyclophosphamide and Tacrolimus for the Prevention of Graft Versus Host Disease in Patients Undergoing Hematopoietic Stem Cell Transplants

Study Overview
=================
Brief Summary
-----------------
This clinical trial evaluates the safety and effectiveness of adding itacitinib to cyclophosphamide and tacrolimus for the prevention of graft versus host disease (GVHD) in patients undergoing hematopoietic stem cell transplant. Itacitinib is an enzyme inhibitor that may regulate the development, proliferation, and activation of immune cells important for GVHD development. Cyclophosphamide and tacrolimus are immunosuppressive agents that may prevent GVHD in patients who receive stem cell transplants. Giving itacitinib in addition to cyclophosphamide and tacrolimus may be more effective at preventing GVHD in patients receiving hematopoietic stem cell transplants.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. Safety lead-in: Determine if shortening tacrolimus administration period to 60 days (day +65 post-hematopoietic cell transplantation [HCT]), when combined with post-transplant cyclophosphamide (PTCy) and itacitinib at a fixed dose level as graft-versus-host disease (GVHD) prophylaxis, is safe and effective after mobilized peripheral blood stem cell (PBSC) allogeneic hematopoietic cell transplantation (HCT) from a matched related/unrelated donor, as assessed by grade 3-4 GVHD as dose limiting toxicity. II. Following the safety lead-in, evaluate the efficacy of PTCy, itacitinib and tacrolimus GVHD prophylaxis, as assessed by 1-year GVHD-free relapse-free survival (GRFS). SECONDARY OBJECTIVES: I. Evaluate the safety of this regimen by assessing: Ia. Adverse events: type, frequency, severity, attribution, time course, duration. Ib. Complications including acute and chronic GVHD, infections and delayed engraftment. II. Estimate overall survival (OS), progression-free survival (PFS), cumulative incidences of relapse/disease progression, and non-relapse mortality (NRM) at 100 days, and 1-year post-transplant. III. Estimate rates of acute and chronic GvHD, infections, and neutrophil recovery. EXPLORATORY OBJECTIVES: I. Donor cell engraftment will be assessed by count monitoring and short tandem repeat (STR) chimerism analysis on days +30 and day +100. II. Describe the kinetics of immune cell recovery. III. Evaluate patient's quality of life on day +100, 6 months and one-year post-HCT. IV. Pharmacokinetics: serial blood sampling will be done to evaluate the steady-state pharmacokinetics of itacitinib after PTCy. V. Describe the kinetics of GVHD biomarkers, JAK-related inflammatory cytokines and STAT phosphorylation. VI. Evaluate and describe the cytokine release syndrome (CRS) post-HCT by assessing the incidence, frequency, and severity of CRS. VII. Obtain a preliminary estimate of gut microbiome diversity at baseline (preferably before fludarabine administration), and then on days +14, +30, and +100. OUTLINE: Patients undergo peripheral blood stem cell infusion on day 0. Patients receive cyclophosphamide intravenously (IV) once daily (QD) on days 3 and 4, itacitinib orally (PO) QD on days 5-100, and tacrolimus IV or PO on days 6-65. After completion of study treatment, patients are followed up at day 180 and 1 year.

Official Title
-----------------
Single Center Pilot Study to Investigate the Efficacy of Adding Itacitinib to Post-Transplant Cyclophosphamide as Graft-Versus-Host Disease Prophylaxis After Reduced Intensity Conditioning Matched Donor Hematopoietic Cell Transplantation With Peripheral Blood Stem Cells as Graft Source

Conditions
-----------------
Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome, Myeloproliferative Neoplasm, Primary Myelofibrosis, Secondary Myelofibrosis

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide
* Drug: Itacitinib
* Procedure: Peripheral Blood Stem Cell Transplantation
* Other: Quality-of-Life Assessment
* Drug: Tacrolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Documented informed consent of the participant and/or legally authorized representative Assent, when appropriate, will be obtained per institutional guidelines Agreement to allow the use of archival tissue from diagnostic tumor biopsies If unavailable, exceptions may be granted with study principal investigator (PI) approval Age: =< 80 years Note: Patients > 70 years of age must have Karnofsky performance status >= 80 and HCT-comorbidity index (CI) =< 2 Karnofsky performance status >= 70% Patients with the following diagnosis, eligible to undergo allogeneic HCT from an 8/8 match related/unrelated donor (A, B, C, DR by high resolution typing) Acute leukemias (acute myeloid leukemia [AML] or acute lymphoblastic leukemia [ALL]) in complete remission with bone marrow (BM) blast of < 5% Myelofibrosis (MF): Primary or secondary with high- or intermediate-2 risk per Dynamic International Prognostic Scoring System (DIPSS) Myelodysplastic syndrome (blast < 10%) Myeloproliferative neoplasm (MPN) other than MF needing HCT Chronic myelomonocytic leukemia (CMML) Total bilirubin =< 2 x upper limit of normal (ULN) (unless has Gilbert's disease) (within 30 days prior to day 1 of protocol therapy unless otherwise stated) Serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) < 5 x ULN (within 30 days prior to day 1 of protocol therapy unless otherwise stated) Creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 30 days prior to day 1 of protocol therapy unless otherwise stated) Left ventricular ejection fraction (LVEF) >= 50% Note: To be performed within 30 days prior to day 1 of protocol therapy If able to perform pulmonary function tests: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and diffusion capacity of the lungs for carbon monoxide (DLCO) (diffusion capacity) >= 50% of predicted (corrected for hemoglobin) (within 30 days prior to day 1 of protocol therapy) If unable to perform pulmonary function tests: O2 saturation > 92% on room air (within 30 days prior to day 1 of protocol therapy) Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis rapid plasma reagin (RPR) (within 30 days prior to day 1 of protocol therapy) If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed OR If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be performed. Viral load must be undetectable Meets other institutional and federal requirements for infectious disease titer requirements Note: Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (within 30 days prior to day 1 of protocol therapy) If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only) Exclusion Criteria: Prior allogeneic HCT Chemotherapy, radiation therapy, biological therapy, immunotherapy within 21 days prior to day 1 of protocol therapy Note: Conditioning regimen within 21 days prior to day 1 of protocol therapy is not considered as an exclusion criterion. Patients on maintenance chemotherapy are not excluded Other investigational drugs for treatment of GVHD History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents Psychological issues, no appropriate caregivers identified, or non-compliant to medication Clinically significant uncontrolled illness Uncontrolled infection (bacterial, viral, fungal) Other active malignancy Females only: Pregnant or breastfeeding Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Ages Eligible for Study
-----------------
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prevention (PBSCs, cyclophosphamide, itacitinib, tacrolimus)<br>Patients undergo peripheral blood stem cell infusion on day 0. Patients receive cyclophosphamide IV QD on days 3 and 4, itacitinib PO QD on days 5-100, and tacrolimus IV or PO on days 6-65. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Itacitinib<br>* Given PO<br>* Other names: INCB039110;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo peripheral blood stem cell infusion<br>* Other names: Peripheral Stem Cell Transplantation;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: Protopic;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Grade III-IV acute graft versus host disease (GVHD) | Acute GVHD will be graded and staged according to Mount Sinai Acute GVHD International Consortium (MAGIC) criteria. | By day 100 | 
| GVHD-free relapse-free survival rate | Will be calculated using the Kaplan-Meier method. | From start of hematopoietic cell transplantation to grade III-IV acute GvHD, chronic GvHD requiring systemic treatment, relapse, or death (from any cause), whichever occurs first, assessed at 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | The toxicity/adverse event information recorded on each subject will include type, severity, duration, and attribution/ association with the study regimen. Tables will be constructed to summarize the observed incidence, severity and type of toxicity, including infection. | Up to 2 years | 
| Overall survival | Will be calculated using the Kaplan-Meier method. | Day of stem cell infusion (day 0) until death or last follow-up, assessed at 100 days | 
| Overall survival | Will be calculated using the Kaplan-Meier method. | Day of stem cell infusion (day 0) until death or last follow-up, assessed at 180 days | 
| Overall survival | Will be calculated using the Kaplan-Meier method. | Day of stem cell infusion (day 0) until death or last follow-up, assessed at 1 year | 
| Progression free survival | Will be calculated using the Kaplan-Meier method. | From the date of stem cell infusion to the date of death, disease relapse/progression, or last follow-up, assessed at 100 days | 
| Progression free survival | Will be calculated using the Kaplan-Meier method. | From the date of stem cell infusion to the date of death, disease relapse/progression, or last follow-up, assessed at 180 days | 
| Progression free survival | Will be calculated using the Kaplan-Meier method. | From the date of stem cell infusion to the date of death, disease relapse/progression, or last follow-up, assessed at 1 year | 
| Relapse/progression | The cumulative incidence will be calculated using the competing risk method. | Day 0 to relapse/progression, assessed at 100 days | 
| Relapse/progression | The cumulative incidence will be calculated using the competing risk method. | Day 0 to relapse/progression, assessed at 180 days | 
| Relapse/progression | The cumulative incidence will be calculated using the competing risk method. | Day 0 to relapse/progression, assessed at 1 year | 
| Non-relapse mortality | The cumulative incidence will be calculated using the competing risk method. | Day 0 until non-disease related death or last follow-up, assessed at 100 days | 
| Non-relapse mortality | The cumulative incidence will be calculated using the competing risk method. | Day 0 until non-disease related death or last follow-up, assessed at 180 days | 
| Non-relapse mortality | The cumulative incidence will be calculated using the competing risk method. | Day 0 until non-disease related death or last follow-up, assessed at 1 year | 
| Rate of acute GVHD | Acute GVHD will be graded and staged according to MAGIC criteria. The first day of acute GVHD onset at a certain grade will be used to calculate the cumulative incidence (grades II-IV). The endpoint will be evaluated from day 0 through 100 days post-transplant. The cumulative incidence will be calculated using the competing risk method. | On day 100 | 
| Rate of chronic GVHD | Chronic graft versus host disease will be evaluated and scored according to National Institutes of Health Consensus Staging. The first day of chronic GVHD onset will be used to calculate the cumulative incidence. The cumulative incidence will be calculated using the competing risk method. | From day 80 through 1 year post-transplant | 
| Rate of infection | Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any. This data will be captured via case report form and will be collected from day -7 to day 120 post-transplant and will follow the same data collection intervals as the toxicity and adverse event data. | Day -7 to day 120 | 
| Rate of hematologic recovery | Absolute neutrophil count >= 0.5 x 10^3/uL achieved and sustained for 3 consecutive lab values on different days with no subsequent decline. Platelets >= 20 K/uL independent of platelet transfusion support (date should reflect no transfusions in previous 7 days, and the first of 3 consecutive lab values on different days). | Up to 2 years | 
| Incidence of cytokine release syndrome | Defined and graded per American Society for Transplantation and Cellular Therapy criteria. | Up to 2 years | 
| Gut microbiome assessment | Gut microbiome diversity will be assessed by the inverse Simpson Index and compared among CBM588-treated/untreated patients; the inverse Simpson index is an ecological measure of α microbial diversity calculated by the inverse of the expected probability of 2 randomly selected bacterial sequences as belonging to the same operational taxonomic unit. | Up to 2 years |