Ruxolitinib Phosphate and Chemotherapy Given Before and After Reduced Intensity Donor Stem Cell Transplant in Treating Patients With Myelofibrosis
Condition: Primary Myelofibrosis; Secondary Myelofibrosis
MeSH terms: Primary Myelofibrosis
Study type: Interventional
Phase: Phase 1

Summary: 
      This pilot clinical trial studies the side effects and best dose of ruxolitinib phosphate
      when given together with chemotherapy before and after a donor stem cell transplant in
      treating patients with myelofibrosis. Ruxolitinib phosphate may stop the growth of cancer
      cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy,
      such as fludarabine phosphate and melphalan, work in different ways to stop the growth of
      cancer cells, either by killing the cells, by stopping them from dividing, or by stopping
      them from spreading. Giving ruxolitinib phosphate together with chemotherapy before and after
      a donor stem cell transplant may help stop the growth of cells in the bone marrow, including
      normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's
      immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor
      are infused into the patient they may help the patient's bone marrow make stem cells, red
      blood cells, white blood cells, and platelets. The donated stem cells may also replace the
      patient?s immune cells and help destroy any remaining cancer cells.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. Among the dose levels tested, to determine the maximum tolerated dose (MTD) and
      recommended phase II dose (RP2D) of ruxolitinib phosphate (ruxolitinib), when given as part
      of reduced intensity allogeneic hematopoietic cell transplant (HCT), in patients with
      myelofibrosis.

      II. To determine if the addition of ruxolitinib is safe by evaluation of toxicities
      including: type, frequency, severity, attribution, time course and duration.

      SECONDARY OBJECTIVES:

      I. To characterize and evaluate hematologic recovery, donor cell engraftment and immune
      reconstitution by cell count and flow cytometry of lymphocyte subsets.

      II. To estimate the cumulative incidence of acute graft-versus-host disease (aGVHD) and
      non-relapse mortality (NRM) at 100-days post transplant.

      III. To estimate the cumulative incidence of chronic GVHD at 1- and 2-years post transplant.

      IV. To estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and
      2-years post transplant.

      V. To characterize changes in aGVHD biomarkers (Reg-3 alpha, soluble tumor necrosis factor
      receptor I [sTNF RI], IL2R alpha), janus associated kinases (JAK)-regulated pro-inflammatory
      cytokines (i.e. IL-6, TNF alpha, CRP, beta 2microglobulin) and STAT3 phosphorylation
      (downstream of JAK signaling) over time and by aGVHD status/grade.

      OUTLINE: This is a dose-escalation study of ruxolitinib phosphate.

      PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -9 to
      -5, melphalan IV over 20 minutes on day -4, and ruxolitinib phosphate orally (PO) twice daily
      (BID) on days -3 to 30 with a taper for 2-3 weeks in the absence of disease progression or
      unacceptable toxicity.

      GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -3 and convert
      to PO daily when the patient is able to tolerate and absorb oral medications. Patients also
      receive sirolimus PO daily beginning on day -3. Treatment continues in the absence of GVHD.

      STEM CELL TRANSPLANT: Patients undergo allogeneic HCT on day 0.

      After completion of study treatment, patients are followed up for 2 years.
    

Intervention name(s): Allogeneic Hematopoietic Stem Cell Transplantation; Fludarabine; Fludarabine Phosphate; Laboratory Biomarker Analysis; Melphalan; Pharmacological Study; Ruxolitinib; Ruxolitinib Phosphate; Sirolimus; Tacrolimus
Intervention type(s): Procedure; Drug; Drug; Other; Drug; Other; Drug; Drug; Drug; Drug
Intervention description(s): Undergo allogeneic HCT; Given IV; Given IV; Correlative studies; Given IV; Correlative studies; Given PO; Given PO; Given PO; Given IV and PO
Other intervention name(s): Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; Fluradosa; 2-F-ara-AMP; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Beneflur; Fludara; SH T 586; Alanine Nitrogen Mustard; CB-3025; L-PAM; L-Phenylalanine Mustard; L-sarcolysin; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine nitrogen mustard; Sarcoclorin; Sarkolysin; WR-19813; INCB-18424; INCB18424; Oral JAK Inhibitor INCB18424; INCB-18424 Phosphate; Jakafi; AY 22989; RAPA; Rapamune; Rapamycin; SILA 9268A; WY-090217; FK 506; Fujimycin; Hecoria; Prograf; Protopic
Intervention MeSH terms: Vidarabine; Sirolimus; Fludarabine; Fludarabine phosphate; Melphalan; Mechlorethamine; Nitrogen Mustard Compounds; Tacrolimus
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment