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Pacritinib, Sirolimus, and Tacrolimus in Preventing Graft Versus Host Disease in Patients with Blood Cancer Undergoing Donor Stem Cell Transplant

Trial Status: Active

This phase I / II trial studies the best dose and side effects of pacritinib when given together with sirolimus and tacrolimus and to see how well they work in preventing graft versus host disease in patients with blood cancer undergoing donor stem cell transplant. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells called graft versus host disease. Giving pacritinib, sirolimus, and tacrolimus after the transplant may stop this from happening.

Inclusion Criteria

  • Patients 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 HSCT
  • Acute leukemia (acute myeloid leukemia [AML] or acute lymphoblastic leukemia [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 Janus kinase 2 (JAK2) inhibitor is allowed up to 4 weeks before day 0 of allogeneic hematopoietic cell transplantation (alloHCT)
  • Hodgkin and non-Hodgkin lymphoma: must have a complete or partial response with prior therapy
  • Left ventricular ejection fraction (LVEF) >= 50% by multigated acquisition scan (MUGA) scan or echocardiogram (ECHO)
  • Forced expiratory volume 1 (FEV1), forced vital capacity (FVC), and adjusted diffusing capacity of the lungs for carbon monoxide (DLCO) >= 50% of predicted values on pulmonary function tests
  • Transaminases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) < 2 times upper limit of normal values
  • Creatinine clearance >= 50 cc/min
  • 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 human immunodeficiency virus (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
  • Corrected QT interval (QTc) > 450 ms per Fridericia’s correction
  • Thrombin time (TT), prothrombin time (PT), or partial thromboplastin time (PTT) > 2 x upper limit of normal
  • Grade 3 or higher recent (within the past 6 months) 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 (within the past 6 months) 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 class III or IV congestive heart failure

Florida

Tampa
Moffitt Cancer Center
Status: ACTIVE
Contact: Joseph Pidala
Phone: 813-745-2556

Minnesota

Minneapolis
University of Minnesota / Masonic Cancer Center
Status: APPROVED
Contact: Shernan Grace Holtan

PRIMARY OBJECTIVES:

I. Determine the lowest biologically active dose of pacritinib that is safe and well tolerated when combined with sirolimus (SIR)/tacrolimus (TAC). (Phase I)

II. Determine if pacritinib (PAC)/SIR/TAC suppresses STAT3 activity in circulating CD4+ T-cells at day +21, to at least 35% phosphorylation. (Phase II)

SECONDARY OBJECTIVES:

I. Investigate whether PAC/SIR/TAC reduces the cumulative incidence of acute graft versus host disease (GVHD) by day +100, compared to our published rate of 43% from SIR/TAC alone.

II. Study the effect of PAC/SIR/TAC on regulatory T cells (Treg), type 1 helper cell (Th1), and type 17 helper cell (Th17) differentiation among circulating T-cells at day +21 and day +100.

III. Determine how PAC/SIR/TAC impacts CD28 and IL-2 receptor signal transduction by measuring S6 (mTOR), H3 ser10 (aurora kinase), and STAT5 phosphorylation in CD4+ T-cells at days +21 and +100.

OUTLINE:

Patients receive pacritinib orally (PO) once daily (QD) or twice daily (BID) on days 0-100. Patients undergo standard of care allogeneic hematopoietic stem cell transplantation (HSCT) on day 0. Patients also receive sirolimus PO daily starting 1 day before HSCT and up to 1 year, and tacrolimus PO or intravenously (IV) daily, starting 3 days before HSCT for up to 50 days. Treatment continues in the absence of disease progression or unexpected toxicity.

Trial Phase Phase I/II

Trial Type Prevention

Lead Organization
Moffitt Cancer Center

Principal Investigator
Joseph Pidala

  • Primary ID MCC-18783
  • Secondary IDs NCI-2017-00594
  • Clinicaltrials.gov ID NCT02891603