A Phase 1 interventional study of Allogeneic Bone Marrow Transplantation and Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia in Remission, Primary Myelofibrosis and Primary Myelofibrosis, Prefibrotic Stage, sponsored by City of Hope Medical Center. Withdrawn at 1 site in United States. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2016-09-14.
Sponsored by City of Hope Medical Center · Phase 1, Interventional, and Supportive care
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.
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PREPARATIVE REGIMEN: Patients receive fludarabine phosphate 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 PO BID on days -3 to 30 tapered to day 60, tacrolimus IV continuously or PO BID on days -3 to 100 , and sirolimus PO QD on day -3 to 100. Treatment continues in the absence of disease progression or unacceptable toxicity.
Procedure: Allogeneic Bone Marrow Transplantation · Procedure: Allogeneic Hematopoietic Stem Cell Transplantation · Drug: Fludarabine Phosphate · Other: Laboratory Biomarker Analysis · Drug: Melphalan · Procedure: Peripheral Blood Stem Cell Transplantation · Other: Pharmacological Study · Drug: Ruxolitinib Phosphate · Drug: Sirolimus · Drug: Tacrolimus
Undergo allogeneic bone marrow transplant
Also known as: Allo BMT, Allogeneic BMT
Undergo allogeneic hematopoeitic stem cell transplant
Also known as: allogeneic stem cell transplantation, HSC, HSCT
Given IV
Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, Oforta, SH T 586
Correlative studies
Given IV
Also known as: 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
Undergo hematopoietic stem cell transplant
Also known as: PBPC transplantation, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplantation
Correlative studies
Given PO
Also known as: INCB-18424 Phosphate
Given PO
Also known as: AY 22989, RAPA, Rapamune, RAPAMYCIN, SILA 9268A, WY-090217
Given IV or PO
Also known as: FK 506, Fujimycin, Prograf, Protopic
Incidence of adverse events recorded using the modified Bearman scale and NCI CTCAE version 4.03
Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Time frame: Up to 2 years
MTD based on dose limiting toxicity recorded using the modified Bearman scale and National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03
Time frame: Up to 60 days post stem cell infusion
Recommended phase II dose of ruxolitinib phosphate, when given in combination with tacrolimus and sirolimus
Time frame: Up to 60 days post stem cell infusion
aGVHD graded and staged according to the Consensus grading
The first day of acute GVHD onset at a certain grade will be used to calculate the cumulative incidence (grades II-IV). Calculated using the Gray method with prior death or relapse considered competing events.
Time frame: Up to 100 days post transplant
Changes in expression levels of biomarkers
For all cytokines/biomarkers that are measured repeatedly over time, a nonparametric smoothing plot will be produced in the first step to view changes in the trend. Expression level changes on the onset of aGVHD from baseline measures will be correlated with aGVHD grade (0-1 vs 2-4 or 0-2 vs 3-4). Furthermore, GVHD biomarkers, Reg-3a, TNF R1, and a composite biomarker panel of 4 proteins (IL-2Ra, TNFR1, IL-8, and hepatocyte growth factor) will be correlated with survival outcomes in a continuous manner or dichotomized manner.
Time frame: Baseline to up to day 100
Chronic graft versus host disease evaluated and scored according to National Health Institute consensus staging
The first day of chronic GVHD onset will be used to calculate the cumulative incidence. Calculated using the Gray method with prior death or relapse considered competing events.
Time frame: Up to 2 years
Engraftment (recovery of granulopoiesis and megakaryopoiesis)
Time frame: Up to 2 years
Incidence of infection
Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any.
Time frame: Up to day 100 post-transplant
Non-relapse mortality defined as death occurring in a patient from causes other than relapse or progression
The cumulative incidence of relapse/progression and non-relapse mortality will be calculated as competing risks using the Gray method. Descriptive statistics will also be used to assess the possible relationship between pre-HSCT disease status and outcomes. As the results of these evaluations are considered hypothesis-generating in nature, the statistics used will not include any formal statistical tests/comparisons.
Time frame: From date of stem cell infusion until non-disease related death, or last follow-up, whichever comes first, assessed up to 2 years
Overall survival
Estimate will be calculated using the Kaplan-Meier method.
Time frame: Time from the day of stem cell infusion until death, or last follow-up, whichever comes first, assessed up to 2 years
Progression-free survival
Estimate will be calculated using the Kaplan-Meier method.
Time frame: date of stem cell infusion to the date of death, disease relapse/progression, or last follow-up, whichever occurs first, assessed up to 2 years
Relapse/progression
The cumulative incidence of relapse/progression and non-relapse mortality will be calculated as competing risks using the Gray method. Descriptive statistics will also be used to assess the possible relationship between pre-hematopoietic stem cell transplant (HSCT) disease status and outcomes. As the results of these evaluations are considered hypothesis-generating in nature, the statistics used will not include any formal statistical tests/comparisons.
Time frame: Up to 2 years
This study is withdrawn, as verified in Sep 2016. You cannot join it, but the record below documents what was studied.
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