Itacitinib, Tacrolimus, and Sirolimus for the Prevention of GVHD in Patients With Acute Leukemia, Myelodysplastic Syndrome, or Myelofibrosis Undergoing Reduced Intensity Conditioning Donor Stem Cell Transplantation

NCT ID: NCT04339101

Last Updated: 2025-03-24

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 59 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-11
• Study Completion Date: 2026-01-20

Brief Summary

This phase IIa trial studies the side effects of itacitinib when given together with standard treatment (tacrolimus and sirolimus), and to see how well it works in preventing graft-versus-host-disease (GVHD) in patients with acute leukemia, myelodysplastic syndrome or myelofibrosis who are undergoing reduced intensity conditioning donor stem cell transplantation. GVHD is a common complication after donor stem cell transplantation, resulting from donor immune cells recognizing recipients' cells and attacking them. Adding itacitinib to tacrolimus and sirolimus may reduce the risk GVHD and ultimately improve overall outcome and survival after donor stem cell transplantation.

Detailed Description

PRIMARY OBJECTIVE:

I. Following a patient safety lead-in, estimate graft-versus-host disease free relapse free (GRFS) survival at 1- year post allogeneic stem cell transplantation (alloHCT).

SECONDARY OBJECTIVES:

I. Estimate the cumulative incidence of acute graft-versus-host disease (aGVHD) and non-relapse mortality (NRM) at 100-days post-transplant.

II. Estimate the cumulative incidence of chronic GVHD at 1- and 2-years post-transplant.

III. Estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and 2-years post-transplant.

IV. Estimate rate of infection and development of second malignancies including lymphoproliferative disorders at 1- and 2-years post-transplant.

V. Assess patients' quality of life (QOL) at day 100 and 1 year post alloHCT.

EXPLORATORY OBJECTIVES:

I. Characterize and evaluate hematologic recovery, donor cell engraftment and immune reconstitution by cell count and flow cytometry of lymphocyte subsets.

II. Characterize changes in aGVHD biomarkers (Reg-3alpha, TNF-RI, and ST2) and a composite biomarker panel (IL2Ralpha, TNF-R1, IL-8, and hepatocyte growth factor), JAK-regulated pro-inflammatory cytokines (i.e., IL-6, TNFalpha, CRP, Beta2 Microglobulin, and IFNgamma) and STAT3 phosphorylation (downstream of JAK signaling) over time and by aGVHD status/grade.

OUTLINE:

REDUCED INTENSITY CONDITIONING (RIC): Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity.

ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT): Patients undergo HSCT on day 0.

GVHD PROPHYLAXIS: Patients receive itacitinib orally (PO) once daily (QD) beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus intravenously (IV) or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then periodically for up to 2 years post- transplantation.

Conditions

Acute Leukemia; Hematologic and Lymphocytic Disorder; Myelodysplastic Syndrome; Primary Myelofibrosis; Secondary Myelofibrosis

Study Design

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

Study Groups

Treatment (itacitinib adipate, tacrolimus, sirolimus)

RIC: Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity.

ALLOGENEIC HSCT: Patients undergo HSCT on day 0.

GVHD PROPHYLAXIS: Patients receive itacitinib PO QD beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus IV or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Fludarabine

Intervention Type: DRUG

Given via infusion

Itacitinib Adipate

Intervention Type: DRUG

Given PO

Melphalan

Intervention Type: DRUG

Given IV

Quality-of-Life Assessment

Intervention Type: OTHER

Ancillary studies

Questionnaire Administration

Intervention Type: OTHER

Ancillary studies

Sirolimus

Intervention Type: DRUG

Given PO

Tacrolimus

Intervention Type: DRUG

Given IV or PO

Interventions

Fludarabine

Given via infusion

Intervention Type: DRUG

Itacitinib Adipate

Given PO

Intervention Type: DRUG

Melphalan

Given IV

Intervention Type: DRUG

Quality-of-Life Assessment

Ancillary studies

Intervention Type: OTHER

Questionnaire Administration

Ancillary studies

Intervention Type: OTHER

Sirolimus

Given PO

Intervention Type: DRUG

Tacrolimus

Given IV or PO

Intervention Type: DRUG

Other Intervention Names

Fluradosa; INCB-039110 Adipate; INCB039110 Adipate; Alanine Nitrogen Mustard; CB-3025; L-PAM; L-Phenylalanine mustard; L-Sarcolysin; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine nitrogen mustard; Sarcoclorin; Sarkolysin; WR-19813; Quality of Life Assessment; AY 22989; RAPA; Rapamune; rapamycin; SILA 9268A; WY-090217; 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
• Performance status: Karnofsky >= 70%
• Patients with neoplastic hematologic disorders with indication of allogeneic transplant according to the standard guidelines as follows:

• Acute leukemia (AL) in first complete response (CR1) or subsequent complete response (CR) or active disease with bone marrow (BM) blast of < 5%
• Myelodysplastic syndrome (MDS) with intermediate-2 or high risk per International Prognostic Scoring System (IPSS) or
• Myelofibrosis; primary or secondary if intermediate-2 or high risk per Dynamic International Prognostic Scoring System (DIPPS)
• All candidates for this study must have a matched related donor (MRD) who is willing to donate BM or peripheral blood stem cells or an 8/8 allele matched unrelated donor (MUD)
• Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease) (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated. In case of active disease, evaluation should be done within 15 days)
• Aspartate aminotransferase (AST) =< 2.5 x ULN (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated. In case of active disease, evaluation should be done within 15 days)
• Alanine aminotransferase (ALT) =< 2.5 x ULN (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated. In case of active disease, evaluation should be done within 15 days)
• Creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated. In case of active disease, evaluation should be done within 15 days)
• Left ventricular ejection fraction (LVEF) >= 50%

• Note: To be performed within 28 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 lung for carbon monoxide (DLCO) (diffusion capacity) >= 50% of predicted (corrected for hemoglobin). If unable to perform pulmonary function tests: oxygen (O2) saturation > 92% on room air.

• Note To be performed within 28 days prior to day 1 of protocol therapy
• Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combination (combo), hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin measurement [RPR])

• If HCV positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed
• 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. 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

• Chemotherapy, radiation therapy, biological therapy, and/or 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
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• Psychological issues, no appropriate caregivers identified, or non-compliant to medication
• Uncontrolled medical or psychiatric disorders which may preclude patients to undergo clinical studies (Discretion of the attending physician)
• Active diarrhea due to inflammatory bowel disease or malabsorption syndrome
• Clinically significant uncontrolled illness
• Active, uncontrolled systemic infection (bacterial, viral, or fungal) requiring antibiotics
• Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
• Diagnosis of Gilbert's disease
• 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 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

Haris Ali

Role: PRINCIPAL_INVESTIGATOR

City of Hope Comprehensive Cancer Center

Locations

City of Hope Medical Center

Duarte, California, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2020-01722

Identifier Type: REGISTRY

Identifier Source: secondary_id

19576

Identifier Type: OTHER

Identifier Source: secondary_id

19576

Identifier Type: -

Identifier Source: org_study_id