Clinical Trial 18783

Cancer Type: Malignant Hematology
Interventions:Alkeran (Melphalan); FK506 (Tacrolimus); Melphalan; Pacritinib; Rapamune (Sirolimus); Rapamycin (Sirolimus); Sirolimus; Tacrolimus; busulfan; fludarabine (Fludarabine phosphate)

Study Type: Prevention
Phase of Study: Phase I/II
Investigators:

  • Joseph Pidala

Overview

Study Title

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

Summary

The purpose of this study is to examine a new approach to preventing a serious problem after transplant called graft vs. host disease (abbreviated as GVHD). This is a single-arm, phase I/II, study of Pacritinib with Sirolimus and Tacrolimus (PAC/SIR/TAC) for the prevention of acute GVHD after matched related and unrelated allogeneic hematopoietic cell transplantation (alloHCT).

Objective

Phase I: 1) Determine the lowest biologically active dose of pacritinib that is safe and well tolerated when combined with SIR/TAC. Phase II: 2) Determine if PAC/SIR/TAC suppresses STAT3 activity in circulating CD4+ T-cells at day +21, 3) Investigate whether PAC/SIR/TAC reduces the cumulative incidence of grade II-IV acute GVHD by day +100, compared our published rate of 43% with SIR/TAC alone14,15, 4) Investigate the impact of PAC/SIR/TAC on Treg, Th1, and Th17 differentiation after allogeneic HCT, and 5) 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.

Inclusion Criteria

  • Age 18 years or older
  • 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: 20% cellular, and peripheral absolute neutrophil count >1000/uL (platelet recovery is not required). Myelodysplasia (MDS) and chronic myeloid leukemia (CML): Must have > Adequate vital organ function.
  • Performance status: Karnofsky Performance Status Score ≥ 80%.
  • Ferritin > 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 > 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.