Itacitinib for the Prevention of Graft Versus Host Disease in Patients Undergoing Donor Stem Cell Transplantation

Itacitinib to Prevent Graft Versus Host Disease

This phase II trial studies how well itacitinib works in preventing graft versus host disease in patients with blood disorders undergoing donor stem cell transplantation. A donor transplantation uses blood-making cells from a family member or unrelated donor to remove and replace abnormal blood cells. Graft versus host disease is a reaction of the donor's immune cells against the patient's body. Itacitinib plus standard treatment may help prevent graft versus host disease in patients who have received a donor stem cell transplantation.

Study Overview

• Status: Withdrawn
• Conditions: Hematopoietic and Lymphoid Cell Neoplasm; Hematologic and Lymphocytic Disorder; Allogeneic Stem Cell Transplant Recipient
• Intervention / Treatment: Drug: Fludarabine; Drug: Methotrexate; Drug: Tacrolimus; Drug: Busulfan; Drug: Itacitinib; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Detailed Description

PRIMARY OBJECTIVE:

I. To estimate the graft-versus (vs.) host disease-free/relapse free survival (GRFS) rate of itacitinib used as prophylaxis to prevent graft versus host disease (GVHD) after allogeneic stem cell transplantation (ASCT) at one year.

SECONDARY OBJECTIVES:

I. To assess the time to neutrophil and platelet engraftment and compare between matched and unmatched donors.

II. To assess safety of itacitinib as measured by non-relapse mortality (NRM) at day 100.

III. To assess the toxicity profile associated with this regimen. IV. To assess the incidence of acute and chronic GVHD. V. To assess the incidence of disease relapse. VI. To assess the incidence of non-relapse mortality. VII. To assess overall survival and progression-free survival. VIII. To assess the incidence of withdrawal syndrome in patients with myelofibrosis.

TERTIARY OBJECTIVES (CORRELATIVE STUDIES):

I. To study immune recovery and cytokines at various time points pre and post-transplant.

II. To study deoxyribonucleic acid (DNA) damage studies in various cells post-transplant.

OUTLINE:

CONDITIONING CHEMOTHERAPY: Patients receive busulfan intravenously (IV) over 3 hours on days -20, -13, and -6 to -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression or unacceptable toxicity.

ALLOGENEIC STEM CELL TRANSPLANTATION: Patients undergo ASCT on day 0.

GVHD PROPHYLAXIS: Patients receive itacitinib orally (PO) once daily (QD) on days -21 to 80. Patients with no evidence of GVHD at day 80 receive a tapered dose of itacitinib until day 90. Patients also receive tacrolimus IV then PO twice daily (BID) for 3 months when able, and methotrexate IV over 30 minutes on days 1, 3, and 6 (day 11 also for patients with a matched unrelated donor).

After completion of study treatment, patients are followed up at 100 days, 6 months, and 1 year.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Karnofsky performance status of at least 70
• Patients with hematological disorders undergoing ASCT with conditioning regimen of timed sequential busulfan and fludarabine
• Human leukocyte antigen (HLA)-identical sibling or 8/8 matched unrelated donor available
• Life expectancy of at least 12 weeks (3 months)
• Direct bilirubin not greater than 1 mg/dL
• Alanine transaminase (ALT) less than or equal 3 x upper limit of normal range
• Serum creatinine less than 1.5 x the upper limit of normal range and creatinine clearance greater than 50 ml/min
• Diffusing capacity for carbon monoxide (DLCO) 65% of predicted corrected for hemoglobin
• Left ventricle ejection fraction (LVEF) of at least 50%
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test
• Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent until at least 30 days after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate

Exclusion Criteria:

• Patients with a comorbidity score > 3. The principal investigator is the final arbiter of eligibility and enrollment of patients with comorbidity score > 3 and may permit enrollment of these patients on individual basis

  • Active or clinically significant cardiac disease including:

    • Congestive heart failure New York Heart Association (NYHA) > class II
    • Active coronary artery disease
    • Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin
    • Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before transplant, or myocardial infarction within 6 months before transplant
• Patients with uncontrolled infections
• Patients with active hepatitis B and C

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Prevention (itacitinib, busulfan, fludarabine, ASCT); CONDITIONING CHEMOTHERAPY: Patients receive busulfan IV over 3 hours on days -20, -13, and -6 to -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC STEM CELL TRANSPLANTATION: Patients undergo ASCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD on days -21 to 80. Patients with no evidence of GVHD at day 80 receive a tapered dose of itacitinib until day 90. Patients also receive tacrolimus IV then PO BID for 3 months when able, and methotrexate IV over 30 minutes on days 1, 3, and 6 (day 11 also for patients with a matched unrelated donor).

Drug: Fludarabine; Given IV; Other Names: Fluradosa; Drug: Methotrexate; Given IV; Other Names: Abitrexate; Folex; Mexate; MTX; Alpha-Methopterin; Amethopterin; Brimexate; CL 14377; CL-14377; Emtexate; Emthexat; Emthexate; Farmitrexat; Fauldexato; Folex PFS; Lantarel; Ledertrexate; Lumexon; Maxtrex; Medsatrexate; Metex; Methoblastin; Methotrexate LPF; Methotrexate Methylaminopterin; Methotrexatum; Metotrexato; Metrotex; Mexate-AQ; Novatrex; Rheumatrex; Texate; Tremetex; Trexeron; Trixilem; WR-19039; Drug: Tacrolimus; Given IV and PO; Other Names: Prograf; Hecoria; FK 506; Fujimycin; Protopic; Drug: Busulfan; Given IV; Other Names: Busulfex; Misulfan; Mitosan; Myeloleukon; Myelosan; 1, 4-Bis[methanesulfonoxy]butane; BUS; Bussulfam; Busulfanum; Busulphan; CB 2041; CB-2041; Glyzophrol; GT 41; GT-41; Joacamine; Methanesulfonic Acid Tetramethylene Ester; Methanesulfonic acid, tetramethylene ester; Mielucin; Misulban; Myeleukon; Mylecytan; Myleran; Sulfabutin; Tetramethylene Bis(methanesulfonate); Tetramethylene bis[methanesulfonate]; WR-19508; Drug: Itacitinib; Given PO; Other Names: INCB039110; INCB 039110; INCB-039110; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo ASCT; Other Names: Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Graft versus host disease (GVHD)-free/relapse free survival rate	The proportion of patients who are alive without disease relapse of GVHD at one year will be reported, along with the corresponding 95% confidence interval. Logistic regression will be used to assess the association between success and clinical and treatment covariates of interest.	At 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to neutrophil engraftment	Will be calculated from the time of transplant and estimated by the Kaplan-Meier method. Distributions will be compared between patients with matched and mismatched donors via the long-rank test.	Up to day 42
Time to platelet engraftment	Will be calculated from the time of transplant and estimated by the Kaplan-Meier method. Distributions will be compared between patients with matched and mismatched donors via the long-rank test.	Up to day 42
To assess the incidence of non-relapse mortality		At day 100
To assess the toxicity profile associated with this regimen		Up to 1 year
To assess the incidence of acute and chronic GVHD.		Up to 1 year
Time to disease relapse	Will be modeled using Cox proportional hazards regression models, considering clinical, demographic, and treatment covariates of interest.	Up to 1 year
Incidence of non-relapse mortality	Will be modeled using Cox proportional hazards regression models, considering clinical, demographic, and treatment covariates of interest. Will be assessed in a competing risks framework, with similar analyses performed.	Up to 1 year
To assess overall survival and progression-free survival.		From day of transplant until day of death, assessed up to 1 year
Incidence of withdrawal syndrome in patients with myelofibrosis		Up to 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune recovery and cytokines	Generalized linear mixed models will be used to assess the association between cytokines over time and treatment and other factors.	Up to 1 year
Deoxyribonucleic acid (DNA) damage studies	The proportion of patients with DNA damage will be reported, and generalized logistic mixed models may be used to assess the association with similar covariates.	Up to 1 year

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 22, 2020
• Primary Completion (ACTUAL): September 22, 2020
• Study Completion (ACTUAL): September 22, 2020

Study Registration Dates

• First Submitted: September 30, 2019
• First Submitted That Met QC Criteria: October 14, 2019
• First Posted (ACTUAL): October 16, 2019

Study Record Updates

• Last Update Posted (ACTUAL): October 29, 2020
• Last Update Submitted That Met QC Criteria: October 27, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Hematologic Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Fludarabine; Methotrexate; Tacrolimus; Busulfan
• Other Study ID Numbers: 2018-0505 (OTHER: M D Anderson Cancer Center); NCI-2019-05753 (REGISTRY: 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