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

NCT ID: NCT05364762

Last Updated: 2025-05-30

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-11-23
• Study Completion Date: 2026-05-22

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.

Conditions

Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome; Myeloproliferative Neoplasm; Primary Myelofibrosis; Secondary Myelofibrosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Cyclophosphamide

Intervention Type: DRUG

Given IV

Itacitinib

Intervention Type: DRUG

Given PO

Peripheral Blood Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo peripheral blood stem cell infusion

Quality-of-Life Assessment

Intervention Type: OTHER

Ancillary studies

Tacrolimus

Intervention Type: DRUG

Given IV or PO

Interventions

Cyclophosphamide

Given IV

Intervention Type: DRUG

Itacitinib

Given PO

Intervention Type: DRUG

Peripheral Blood Stem Cell Transplantation

Undergo peripheral blood stem cell infusion

Intervention Type: PROCEDURE

Quality-of-Life Assessment

Ancillary studies

Intervention Type: OTHER

Tacrolimus

Given IV or PO

Intervention Type: DRUG

Other Intervention Names

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

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)

• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

City of Hope Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Monzr M Al Malki

Role: PRINCIPAL_INVESTIGATOR

City of Hope Medical Center

Locations

City of Hope Medical Center

Duarte, California, United States

Countries

United States

Other Identifiers

NCI-2022-03765

Identifier Type: REGISTRY

Identifier Source: secondary_id

21776

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA033572

Identifier Type: NIH

Identifier Source: secondary_id

View Link

21776

Identifier Type: -

Identifier Source: org_study_id