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
Overview
- Phase
- Phase 1
- Intervention
- Allogeneic Bone Marrow Transplantation
- Conditions
- Acute Myeloid Leukemia in Remission
- Sponsor
- City of Hope Medical Center
- Locations
- 1
- Primary Endpoint
- Incidence of adverse events recorded using the modified Bearman scale and NCI CTCAE version 4.03
- Status
- Withdrawn
- Last Updated
- 9 years ago
Overview
Brief Summary
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.
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 (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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Primary or secondary myelofibrosis intermediate or high risk by Dynamic International Prognostic Scoring System 26 (DIPSS26) in chronic or accelerated phase
- •Transformed acute myeloid leukemia (AML) with marrow fibrosis is allowed, if AML is in complete remission after induction therapy
- •Patients with a performance status of \>= 70% on the Karnofsky scale
- •Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for 1 year following transplant as per City of Hope standard operating procedure, (SOP) for allogeneic transplantation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
- •Bone marrow and peripheral blood studies must be available for confirmation of diagnosis; cytogenetics, flow cytometry, and molecular studies (such as JAK-2, myeloproliferative leukemia \[MPL\] and calreticulin \[CALR\] mutational status) will be obtained as per standard practice
- •Bone marrow aspirates/biopsies should be performed within 23 ± 7 days from registration to confirm disease remission status
- •All candidates for this study must have a human leukocyte antigen (HLA) (A, B, C, DR) identical siblings who is willing to donate bone marrow or primed blood stem cells or an 8/8 allele-matched unrelated donor
- •All ABO blood group combinations of the donor/recipient are acceptable since even major ABO compatibilities can be dealt with by various techniques (red cell exchange or plasma exchange)
- •A cardiac evaluation with an electrocardiogram showing no ischemic changes or abnormal rhythm and an ejection fraction of 50% established by multi gated acquisition scan (MUGA) or echocardiogram
- •Patients must have creatinine of less than or equal to 1.5 mg/dL or creatinine clearance \> 60 ml/min
Exclusion Criteria
- •Patients should not have any uncontrolled illness including ongoing or active infection
- •Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib
- •Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with ruxolitinib
- •Patients with active 2nd malignancies other than myelofibrosis, AML, excised skin cancer, early stage cervical and prostate cancer
- •Previous allogeneic hematopoietic stem cell transplantation
- •Any psychiatric, social or compliance issues that, in the treating physician opinion, will interfere with completion of the transplant treatment and follow up
- •Patients who have been treated with chemotherapy or radiation within two weeks of planned study enrollment; this does not include hydroxyurea or ruxolitinib, which may be continued until start of conditioning therapy
- •Non-compliance defined as any subject, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
Arms & Interventions
Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
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.
Intervention: Allogeneic Bone Marrow Transplantation
Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
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.
Intervention: Allogeneic Hematopoietic Stem Cell Transplantation
Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
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.
Intervention: Fludarabine Phosphate
Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
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.
Intervention: Laboratory Biomarker Analysis
Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
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.
Intervention: Melphalan
Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
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.
Intervention: Peripheral Blood Stem Cell Transplantation
Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
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.
Intervention: Pharmacological Study
Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
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.
Intervention: Ruxolitinib Phosphate
Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
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.
Intervention: Sirolimus
Supportive care (ruxolitinib phosphate, tacrolimus, sirolimus)
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.
Intervention: Tacrolimus
Outcomes
Primary Outcomes
Incidence of adverse events recorded using the modified Bearman scale and NCI CTCAE version 4.03
Time Frame: Up to 2 years
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.
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
Secondary Outcomes
- aGVHD graded and staged according to the Consensus grading(Up to 100 days post transplant)
- Changes in expression levels of biomarkers(Baseline to up to day 100)
- Chronic graft versus host disease evaluated and scored according to National Health Institute consensus staging(Up to 2 years)
- Engraftment (recovery of granulopoiesis and megakaryopoiesis)(Up to 2 years)
- Incidence of infection(Up to day 100 post-transplant)
- Non-relapse mortality defined as death occurring in a patient from causes other than relapse or progression(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(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(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(Up to 2 years)