Secondary Acute Myeloid Leukemia Clinical Trial
Official title:
A Phase I Trial of Ruxolitinib Combined With Tacrolimus and Sirolimus as Acute Graft-versus-Host Disease (aGVHD) Prophylaxis During Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Patients With Myelofibrosis
This phase I trial studies the side effects and best dose of ruxolitinib phosphate when given together with tacrolimus and sirolimus in preventing acute graft-versus-host disease during reduced intensity donor hematopoietic cell transplant in patients with myelofibrosis. Sometimes transplanted cells from a donor can attack the normal tissue of the transplant patient called graft-versus-host disease. Ruxolitinib phosphate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It may also reduce graft-versus-host disease by reducing inflammation and immune modulation. Giving ruxolitinib phosphate together with tacrolimus and sirolimus after transplant may prevent graft-versus-host disease.
PRIMARY OBJECTIVES:
I. Among the dose levels tested, to determine the maximum tolerated dose (MTD) and
recommended phase II dose (RP2D) of ruxolitinib (ruxolitinib phosphate), when given in
combination with tacrolimus and sirolimus (TAC/SIR) as acute graft-versus-host disease
(aGVHD) prophylaxis as part of reduced intensity allogeneic hematopoietic cell transplant
(HCT), in patients with myelofibrosis or other related myeloid neoplasm with marrow
fibrosis.
SECONDARY OBJECTIVES:
I. To determine if the addition of ruxolitinib, to the standard aGVHD prophylactic regimen
of TAC/SIR, is safe by evaluation of toxicities including: type, frequency, severity,
attribution, time course and duration.
II. To estimate the cumulative incidence of 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 characterize and evaluate hematologic recovery, donor cell engraftment and immune
reconstitution by cell count and flow cytometry of lymphocyte subsets.
V. To estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and
2-years post transplant.
VI. To characterize changes in aGVHD biomarkers (regenerating islet-derived 3-alpha
[Reg-3alpha], soluble tumor necrosis factor receptor I [sTNF RI], interleukin 2 receptor
alpha [IL2Ralpha]), Janus-associated kinase (JAK)-regulated pro-inflammatory cytokines (i.e.
interleukin [IL]-6, tumor necrosis factor [TNF] alpha, C-reactive protein [CRP], beta 2
microglobulin) and signal transducer and activator of transcription 3 (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 and melphalan IV over 20 minutes on day -4. Beginning greater than 48 hours after
completion of melphalan, patients undergo peripheral blood stem cell or bone marrow
transplant according to standard guidelines on day 0.
GVHD PROPHYLAXIS: Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) on
days -3 to 30 tapered to day 60, tacrolimus IV continuously or PO BID on days -3 to 100 ,
and sirolimus PO once daily (QD) on day -3 to 100. Treatment continues in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up 2 years.
;
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Supportive Care
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