Exploring the Potential of Dual Kinase JAK 1/2 Inhibitor Ruxolitinib (INC424) With Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Patients With Myelofibrosis
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 21
- 试验地点
- 8
- 主要终点
- Percent of Participants With 100-day Survival Without Graft Failure
研究概览
简要总结
The purpose of this study is to find out if giving the study drug Ruxolitinib (INC424) prior to a combination of other chemotherapeutic drugs (Fludarabine and Busulfan) before infusing another person's hematopoietic stem cells (bone marrow transplantation) will be successful in people who have advanced primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF), collectively known as myelofibrosis (MF). MF is a disorder in which bone marrow tissue develops in abnormal sites because the bone marrow itself undergoes fibrosis or scarring. This study plans to evaluate whether adding the drug Ruxolitinib will further aid in reducing pre-transplant spleen size, improve physical performance levels and reduce adverse events (side effects) related to the transplant. Ruxolitinib is a drug that is approved by the FDA for the treatment of patients with advanced forms of myelofibrosis. Using Ruxolitinib prior to stem cell transplantation is experimental.
详细描述
A two- stage Simon Phase II study will be conducted in each of two groups of patients: related and unrelated donor transplants. In each donor transplant group, the first stage of this design will include 11 patients evaluated for death or graft failure by 100 days post-transplant. In each stratum, we will enroll additional patients (up to 20%) of stratum total to take into account exclusions due to donor failure (such as donor deemed unsuitable for stem cell donation due to medical or other reasons) only. Those patients who have toxicities related to Ruxolitinib and not been able to reach HCT due to these toxicities will be included in the estimation of overall failure rates. Only those patients who are excluded based on donor related issues without any regimen related complications will be excluded from the estimation of failure rates. However, all data on these patients will be reported.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented diagnosis of primary myelofibrosis according to WHO criteria or post PV myelofibrosis or post ET myelofibrosis as per IWG-MRT criteria
- •Age 18-70 years
- •Intermediate-2/ high-risk disease as per Dynamic IPSS (DIPSS) criteria OR Intermediate-1 risk disease with one of the following additional unfavorable features known to impact the survival adversely
- •Red cell transfusion dependency
- •Unfavorable Karyotype
- •Platelet count <100 x 109/l
- •Blasts in the PB and BM ≤10% prior to study enrollment
- •Availability of a suitable matched related (6/6 or 5/6) or unrelated donor (10/10 or 9/10 antigen or allele matched).
- •Able to give informed written consent
- •ECOG Performance status of 0-
- •Life expectancy >3 months
- •Off all MF-directed therapy including investigational agents for at least 2 weeks prior to study enrollment and recovered from all toxicities*
- •Adequate organ function
- •Adequate renal function - creatinine <1.5 x IULN
- •Adequate hepatic function - AST/ALT <2.5 x IULN, Total Bilirubin <1.5 x IULN
- •Adequate hematopoietic function - Platelet ≥50 x 109/l and ANC ≥1.0 x 109/l
- •LVEF >40% (MUGA or echocardiogram) Normal per Institutional standard
- •Adequate pulmonary function with DLCO >50%
- •A patient who has been on stable dose of Ruxolitinib and has received ruxolitinib ≤6 months prior to the study entry will be considered potentially eligible for the study with the caveat that there is no evidence of loss of response (>5cm increase in spleen size from the nadir).
排除标准
- •Any previous JAK2 inhibitor treatment prior to study enrollment, with the exception of Ruxolitinib
- •Hypersensitivity to JAK inhibitor
- •Clinical or laboratory evidence of cirrhosis
- •Prior allogeneic transplant for any hematopoietic disorder
- •>20% blast in the PB or BM prior to HCT or had leukemic transformation (>20% blasts in PB or BM any time prior to HCT)
- •Syngeneic donor
- •Cord Blood transplant
- •Active uncontrolled infection
- •H/o another malignancy within 5-years of date of HCT except h/o basal cell or squamous cell carcinoma of skin or PV or ET
- •Known HIV positive
- •Pregnancy at the time of BMT
- •Any other concurrent illness which in investigator's opinion puts the patient at excessive risk of treatment related toxicities
- •Unable to give informed consent
- •Active infection with hepatitis A,B or C virus
- •Subjects who require therapy with a strong CYP3A4 inhibitor prior to enrollment to this study
研究组 & 干预措施
Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)
Ruxolitinib (INC424) tablets will be started 62 days (day -67) prior to start of conditioning chemotherapy. The starting dose of Ruxolitinib will be determined according to baseline platelet count and will be modified according to platelet count at follow-up. The drug will be given in the maximum tolerated dose as defined in the protocol for 56 days, followed by 4 days of taper, and will be stopped completely at the planned start of conditioning therapy (starting on day -5) i.e. 5 days prior to stem cell infusion. The drug will be supplied as 5 mg tablets.
干预措施: Ruxolitinib Pre- Hematopoietic cell transplantation (HCT) (Drug)
结局指标
主要结局
Percent of Participants With 100-day Survival Without Graft Failure
时间窗: Day 100-post allogeneic stem cell transplantation
The feasibility of combining Ruxolitinib (INC424) with a Reduced intensity conditioning (RIC) regimen likely to produce success post transplantation, success being defined as patient being alive, and without graft failure at day 100-post allogeneic stem cell transplantation (in patients who receive (a) related donor transplant and in those who receive (b) an unrelated donor transplant.
次要结局
- Time to Neutrophil Recovery(up to 4 years)
- Platelet Recovery(up to 4 years)
- Percent of Participants With Non-relapse Mortality (NRM)(1-year post transplant)
- Number of Participants With Remission Status at 6 Months Post Transplant(6 months post transplant)
- Number of Participants With Remission Status at 12 Months Post Transplant(12 months post transplant)
- Number of Participants With Relapse/Progression (Defined as Per IWG-MRT Criteria)(1-year post transplant)
- Percent of Participants With Graft Versus Host Disease (GvHD)(1-year post transplant)
- Chimerism Studies(100 days post transplant)
- Number of Participants With Remission Status According to IWG-MRT Criteria(Day 100 post transplant)
- Number of Participants With Progression-free Survival(1-year post transplant)
- Number of Overall Survival(1-year post transplant)
- Mean Change in the Brief Fatigue Inventory Score(baseline and 48 months)
- Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning(100 days post transplant)
- Association of Cytokines Levels With Acute and Chronic GvHD(100 days post transplant)
研究者
John Mascarenhas
Associate Professor
Icahn School of Medicine at Mount Sinai