PRIMARY OBJECTIVES:
I. To evaluate the efficacy of itacitinib in preventing the occurrence of death, development of severe (grade 3 or higher) cytokine release syndrome (CRS) or grade 1-2 CRS that requires additional CRS-directed treatment (e.g. tocilizumab, silutximab or similar) between day 0 and day 14 after nonmyeloablative related partially human leukocyte antigen (HLA)-mismatched PBSCT with high-dose post-transplant cyclophosphamide (PTCy) in older patients (age ≥ 60 years).
II. To identify the safe PTCy-based immunosuppressive regimen that incorporates itacitinib with tacrolimus and a reduced duration of immunosuppression with mycophenolate (MMF) in patients age 60 and older who are undergoing nonmyeloablative (NMA), related donor, partially HLA-mismatched peripheral blood stem cell transplant (PBSCT).
SECONDARY OBJECTIVES:
I. To determine the incidence and grade of CRS after itacitinib administration in context of PTCy-based graft versus host disease (GVHD) prophylaxis.
II. To evaluate the overall safety, tolerability and toxicity of itacitinib given in the context of PTCy-based immunosuppressive regimen with tacrolimus and a reduced duration of immunosuppression with MMF in patients age 60 and older who are undergoing NMA, related donor, partially HLA-mismatched PBSCT (acute GVHD [aGVHD], non-relapse mortality [NRM], graft failure, lack of neutrophil engraftment, and other treatment related toxicities).
III. In patients eligible for reduced-duration immunosuppression, estimate the incidences of severe acute grade III or higher GVHD, chronic GVHD (overall and by extent) requiring additional immunosuppressive therapy (IST), graft failure, relapse, and NRM, in the expansion cohort plus patients treated with the same regimen during the regimen-finding phase of the study and overall.
IV. Estimate the cumulative incidence of systemic steroid initiation, the cumulative incidence of non-steroid immunosuppression use, and the cumulative incidence of discontinuation of systemic immunosuppression for GVHD treatment by 1 year and 2 years after PBSCT for the group overall and for patients with shortened-duration immunosuppression; and describe the number and types of systemic immunosuppression used for GVHD treatment, in the expansion cohort plus patients treated with the same regimen during the regimen-finding phase of the study and overall.
V. Estimate the progression-free survival, disease-free survival, overall survival, GVHD-free relapse-free survival, and chronic GVHD-free relapse-free survival after transplantation, in the expansion cohort plus patients treated with the same regimen during the regimen-finding phase of the study and overall.
EXPLORATORY OBJECTIVES:
I. To examine serial changes in defined plasma-derived proteomic biomarkers (IL-2Ralpha, IL-6, TNFR-1, ST2, elafin, REG3alpha, and CXCL9) and cytokines (IL1, IL-6) post-transplant, and their effect on the GVHD development.
II. To characterize the immune recovery after PTCy-based allografting using itacitinib, both by flow cytometry and transcriptional analysis.
OUTLINE: Patients are assigned to 1 of 4 post-transplant immunosuppression regimens.
REGIMEN 1: Patients receive fludarabine intravenously (IV) over 30-60 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5 and undergo total body irradiation (TBI) on day -1 and PBSCT per standard of care. After transplantation, patients also receive high dose cyclophosphamide IV over 1-2 hours on days 3 and 4, itacitinib orally (PO) once daily (QD) on days -3 to 90, mycophenolate mofetil PO or IV thrice daily (TID) on days 5-35, and tacrolimus PO or IV twice daily (BID) on days 5-90 in the absence of disease progression or unacceptable toxicity.
REGIMEN 2: Patients receive fludarabine IV over 30-60 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5 and undergo TBI on day -1 and PBSCT per standard of care. After transplantation, patients also receive high dose cyclophosphamide IV over 1-2 hours on days 3 and 4, itacitinib PO QD on days -3 to 90, mycophenolate mofetil PO or IV TID on days 5-25, and tacrolimus PO or IV BID on days 5-90 in the absence of disease progression or unacceptable toxicity.
REGIMEN 3: Patients receive fludarabine IV over 30-60 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5 and undergo TBI on day -1 and PBSCT per standard of care. After transplantation, patients also receive high dose cyclophosphamide IV over 1-2 hours on days 3 and 4, itacitinib PO QD on days -3 to 90, mycophenolate mofetil PO or IV TID on days 5-15, and tacrolimus PO or IV BID on days 5-90 in the absence of disease progression or unacceptable toxicity.
REGIMEN 4: Patients receive fludarabine IV over 30-60 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5 and undergo TBI on day -1 and PBSCT per standard of care. After transplantation, patients also receive high dose cyclophosphamide IV over 1-2 hours on days 3 and 4, itacitinib PO QD on days -3 to 90 and tacrolimus PO or IV BID on days 5-90 in the absence of disease progression or unacceptable toxicity.
Additionally, patients undergo computed tomography (CT) of sinuses and chest at screening and blood sample collection and bone marrow aspiration and biopsy throughout the study.
After completion of study treatment, patients are followed at months 4, 6, and 9 and at 1 year then every 6 months to 1 year for up to year 2.
