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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Primary Myelofibrosis; Chronic Myelomonocytic Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Secondary Myelofibrosis
• Intervention / Treatment: Other: Quality-of-Life Assessment; Drug: Cyclophosphamide; Drug: Tacrolimus; Drug: Itacitinib; Procedure: Peripheral Blood Stem Cell Transplantation

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope Medical Center
      • Contact: Monzr M. Al Malki; Phone Number: 626-218-2405; Email: malmaki@coh.org
      • Principal Investigator: Monzr M. Al Malki

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Prevention (PBSCs, cyclophosphamide, itacitinib, tacrolimus); 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.

Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Tacrolimus; Given IV or PO; Other Names: Prograf; Hecoria; FK 506; Fujimycin; Protopic; Drug: Itacitinib; Given PO; Other Names: INCB039110; INCB 039110; INCB-039110; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo peripheral blood stem cell infusion; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant; PERIPHERAL BLOOD STEM CELL TRANSPLANT; Peripheral Blood

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

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Monzr M Al Malki, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2022
• Primary Completion (Estimated): April 28, 2024
• Study Completion (Estimated): April 28, 2024

Study Registration Dates

• First Submitted: May 3, 2022
• First Submitted That Met QC Criteria: May 3, 2022
• First Posted (Actual): May 6, 2022

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 20, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Lymphoid; Leukemia, Myeloid; Chronic Disease; Myelodysplastic Syndromes; Primary Myelofibrosis; Leukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myeloproliferative Disorders; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Calcineurin Inhibitors; Cyclophosphamide; Tacrolimus
• Other Study ID Numbers: 21776 (Other Identifier: City of Hope Medical Center); P30CA033572 (U.S. NIH Grant/Contract); NCI-2022-03765 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No