Itacitinib for the Prevention of Graft Versus Host Disease

PRIMARY OBJECTIVE:

I. To compare the 100-day acute grade 2-4 GvHD rate to matched controls.

SECONDARY OBJECTIVES:

I. To compare the 1-year rate of GvHD-free, relapse-free survival to matched controls.

II. To assess the time to neutrophil and platelet engraftment. III. To assess the toxicity profile associated with this regimen. IV. To assess the incidence of severe grade 3-4 acute GVHD. V. To assess the incidence of limited, extensive, and moderate to severe chronic GVHD.

VI. To assess the incidence of disease relapse. VII. To assess the incidence of non-relapse mortality. VIII. To assess overall survival and progression-free survival. IX. To assess immunosuppression discontinuation rate.

TERTIARY OBJECTIVE (CORRELATIVE STUDY):

I. Immune recovery and cytokines at various time points pre- and post- transplant

OUTLINE:

CONDITIONING: Patients receive busulfan intravenously (IV) over 3 hours on days -20, -13, and -6 to -3, thiotepa IV on day -7, and fludarabine IV over 1 hour on days -6 to -3.

STEM CELL TRANSPLANT: Patients undergo stem cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4. Patients also receive itacitinib orally (PO) once daily (QD) on days 5-60 in the absence of disease progression or unacceptable toxicity. Beginning day 5 after stem cell transplant, patients also receive tacrolimus IV over 24 hours until able to tolerate oral tacrolimus, whereby patients then receive tacrolimus PO twice daily (BID).

After completion of study intervention, patients are followed up at days 100, 180, and 365 after stem cell transplant.

Inclusion criteria

• Patients 18 years to less than or equal to 70 years
• English and non-English speaking patients are eligible
• Karnofsky performance status of at least 70
• Patients with hematological disorders undergoing allogeneic stem cell transplant (ASCT) with conditioning regimen of fractionated busulfan, thiotepa and fludarabine
• Donor will be matched at HLA A, B, C and DR at allele level. Donor will be either HLA-identical sibling or at least 7/8 matched unrelated donor, or a haploidentical related 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
• Creatinine clearance >/= 60 ml/ min
• Diffusing capacity for carbon monoxide (DLCO) 50% of predicted corrected for hemoglobin
• Left ventricular 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 form (ICF) until at least 30 days after the last dose of study drug. Recommended methods of birth control are:

• Hormonal contraception (birth control pills, patches, or rings)
• Intrauterine device (IUD)
• Birth control injections
• Double barrier methods (diaphragm with spermicidal gel or condoms with birth control foam)
• Sterilization of patient or partner ("tubes tied" or vasectomy)
• Patients enrolled on this study may be enrolled on other IND studies at the discretion of the PI

Exclusion criteria

• Patients with acute leukemia in the first complete remission and chronic myeloid leukemia in the first chronic phase during the initial enrollment of 6 patients
• Patients with toxicities (Grade > 1) unresolved from prior treatment (including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, or surgery)
• Haploidentical recipients should not have donor-specific antibodies (DSA)
• 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 active hepatitis B and C
• Patients with cognitive impairments and/or any serious unstable pre-existing medical condition or psychiatric disorder that can interfere with safety or with safety or with obtaining informed consent or compliance with study procedures