A Phase I/II GVHD Prevention Trial Combining Pacritinib With Sirolimus-Based Immune Suppression

GVHD is a common problem that occurs after transplant despite the use of standard immune
suppressive medications (these are called sirolimus and tacrolimus). GVHD can result in skin
rash, nausea, vomiting, diarrhea, and liver damage. Severe GVHD can be life-threatening.

In this study, investigators will add a medication called pacritinib to the combination of
sirolimus and tacrolimus to see if this approach can more effectively prevent GVHD.
Pacritinib is a medicine used to treat a disease of the bone marrow called myelofibrosis
Pacritinib turns off a switch in cells called Janus Kinase 2 (JAK2). Pacritinib is an
investigational medicine used in several clinical trials and not FDA approved. JAK2 is an
important regulator of inflammation. This inflammation is thought to contribute to GVHD.
Pacritinib is able to turn this inflammation off by inhibiting JAK2. Research has shown that
blocking JAK2 prevents GVHD in mice and also reduces severe GVHD in transplant patients.
Doctors at Moffitt have identified that inflammation from JAK2 is an important cause of GVHD,
and is present well before patients develop GVHD symptoms. This trial will study how well
pacritinib turns off inflammation during the transplant and if it prevents GVHD when added to
our standard medicines.

Pacritinib will begin the day of the participant's transplant (Day 0) and will continue until
70 days after the transplant.

Sirolimus will be given the day before transplant and continued daily for at least one year.

Tacrolimus will begin 3 days before transplant and will be given for at least 50 days.

Inclusion Criteria:

- Must have an available 8/8 HLA-A, -B, -C, and -DRB1 matched-related or unrelated donor
allogeneic hematopoietic peripheral blood stem cell graft.

- Signed informed consent.

- Acute myeloid leukemia, myelodysplasia, acute lymphoblastic leukemia, chronic myeloid
leukemia, chronic lymphocytic leukemia, myeloproliferative neoplasms, Hodgkin
lymphoma, or non-Hodgkin lymphoma requiring a matched allogeneic hematopoietic stem
cell transplantation (HSCT). Acute Leukemia (AML or ALL) must be in complete remission
defined as: <5% marrow blasts with no morphologic evidence of leukemia, no peripheral
blasts, marrow >20% cellular, and peripheral absolute neutrophil count >1000/uL
(platelet recovery is not required). Myelodysplasia (MDS) and chronic myeloid leukemia
(CML): Must have <5% marrow blasts. Myeloproliferative neoplasms (MPN): Must have <5%
peripheral / marrow blasts. Note: Prior use of a JAK2 inhibitor is allowed up to 4
weeks before day 0 of alloHCT. Hodgkin and non-Hodgkin lymphoma: Must have
chemosensitive disease.

- Adequate vital organ function.

- Performance status: Karnofsky Performance Status Score ≥ 80%.

Donor Eligibility:

- Eligible donors will include healthy sibling, relative or unrelated donors that are
matched with the patient at HLA-A, B, C, and DRB1 by high resolution typing as defined
by the Collaborative Trials Network.

Exclusion Criteria:

- Active infection not controlled with appropriate antimicrobial therapy.

- History of HIV, hepatitis B, or active hepatitis C infection.

- Anti-thymocyte globulin, alemtuzumab, bortezomib, or post-transplant cyclophosphamide
as part of GVHD prophylaxis.

- Sorror's co-morbidity factors with total score >4.

- Any patient anticipating or scheduled to receive a tyrosine kinase inhibitor, FLT3
inhibitor, or JAK2 inhibitor (outside of this study) post-HCT.

- QTc>450ms per Fridericia's correction.

- Thrombin time (TT), prothrombin time (PT), or partial thromboplastin time (PTT) >2x
upper limit of normal (ULN).

- Grade 3 or higher recent (within the past 6 months) or ongoing non-QTc cardiac adverse
events/comorbidities.

- Grade 3 or higher recent or ongoing cardiac dysrhythmias, family history of long QT.

syndrome, or serum potassium <3.0 mEq/L that is persistent and refractory to correction.

- Grade 3 or higher recent or ongoing bleeding events.

- Symptomatic or uncontrolled cardiovascular disease, myocardial infarction or
severe/unstable angina within the past 6 months, or New York Heart Association (NYHA)
Class III or IV congestive heart failure.