NCT02370706已完成1 期
A Phase Ib, Multi-center, Open-label, Dose-escalation Study of PIM447 in Combination With Ruxolitinib (INC424) and LEE011 Administered Orally in Patients With Myelofibrosis
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Incidence of dose limiting toxicities during the first cycle of study treatment
研究概览
简要总结
This is a phase Ib study with the primary purpose is to estimate the MTD and/or RDE for the triple combination of PIM447, formerly LGH447, plus ruxolitinib and LEE011 as well as for the doublets, PIM447 plus ruxolitinib, and LEE011 plus ruxolitinib, in patients with myelofibrosis (MF). Each regimen will be assessed for safety, tolerability, pharmacokinetics (PK) and pharmacodynamic effects, and preliminary anti-myelofibrosis activity, including changes in spleen volume, JAK2V617F allele burden, and hematologic response.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Parallel
- 主要目的
- Health Services Research
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 to
- •Patient must be diagnosed with JAK2V617F-positive primary or secondary MF.
- •Dose-escalation and Expansion parts: Patients with a < 35% reduction in spleen volume by MRI/CT or < 50% reduction in spleen size by physical exam, with or without corresponding symptomatic improvement, after at least 6 months of treatment with single agent ruxolitinib at an optimal dose level in line with the label recommendations. Expansion parts only: Ruxolitinib-naive patients and patients who have been previously treated with single agent ruxolitinib and are relapsed and/or refractory.
- •Patients must have splenomegaly measuring at least 5 cm by MRI at baseline.
- •Have adequate bone marrow function:
- •Platelets ≥ 100,000 mm3 without the assistance of growth factors or platelet transfusions
- •Absolute Neutrophil Count (ANC) ≥ 1500/mm3 without growth factor support within 7 days prior to testing
- •Hemoglobin ≥ 9 g/dL.
排除标准
- •Systemic antineoplastic therapy (including unconjugated therapeutic antibodies, toxin immunoconjugates, and alpha-interferon) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment
- •Major surgery within 2 weeks before the first dose of either study drug.
- •Patients who have had splenic irradiation within 2 weeks prior to Screening or prior splenectomy.
- •Patients with AML, MDS, or peripheral blasts ≥ 10 %
- •Prior autologous or allogeneic stem cell transplant at any time.
- •Patients who are currently receiving treatment with a prohibited medication that cannot be discontinued at least one week prior to the start of treatment:
- •substrates of CYP3A4/5, CYP2B6 or CYP2D6 that have a narrow therapeutic window
- •strong inhibitors of CYP3A4/5 or CYP2D6
- •potent inducers of CYP3A4/5 or CYP2D6
- •Serum total bilirubin > 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome who are excluded if the total bilirubin is > 3.0 x ULN or direct bilirubin > 1.5 x ULN, or aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or ALT (SGPT) > 3 x ULN, except in patients with MF involvement of the liver who are excluded if AST or ALT > 5 x ULN.
- •Serum creatinine > 1.5 x ULN or calculated creatinine clearance < 60 ml/min according to Cockcroft-Gault equation
- •Electrolyte abnormalities CTCAE grade ≥ 2 (e.g. serum potassium, magnesium and calcium) unless they can be repleted during screening and are deemed not clinically significant by the Investigator.
研究组 & 干预措施
Dose Escalation Arm 2
Experimental
干预措施: Ruxolitinib (Drug)
Dose Escalation Arm 2
Experimental
干预措施: LEE011 (Drug)
Dose Escalation Arm 1
Experimental
干预措施: PIM447 (Drug)
Dose Escalation Arm 1
Experimental
干预措施: Ruxolitinib (Drug)
Dose Escalation Arm 3
Experimental
干预措施: PIM447 (Drug)
Dose Escalation Arm 3
Experimental
干预措施: Ruxolitinib (Drug)
Dose Escalation Arm 3
Experimental
干预措施: LEE011 (Drug)
Dose Expansion Arm 1
Experimental
干预措施: PIM447 (Drug)
Dose Expansion Arm 1
Experimental
干预措施: Ruxolitinib (Drug)
Dose Expansion Arm 2
Experimental
干预措施: Ruxolitinib (Drug)
Dose Expansion Arm 2
Experimental
干预措施: LEE011 (Drug)
Dose Expansion Arm 3
Experimental
干预措施: PIM447 (Drug)
Dose Expansion Arm 3
Experimental
干预措施: Ruxolitinib (Drug)
Dose Expansion Arm 3
Experimental
干预措施: LEE011 (Drug)
结局指标
主要结局
Incidence of dose limiting toxicities during the first cycle of study treatment
时间窗: Cycle 1 (28 days)
To estimate the maximum tolerated dose and/or recommended dose for expansion for each of the following three treatment arms in patients with myelofibrosis (MF): PIM447 plus ruxolitinib (doublet), LEE011 plus ruxolitinib (doublet), PIM447 plus ruxolitinib and LEE 011 (triple combination).
次要结局
- Change in bone marrow fibrosis and histomorphology(Approximately 27 months (end of study))
- Changes in ratio of mutant to wild type JAK2 alleles (i.e. allele burden)(Approximately 27 months (end of study))
- Change in platelets, neutrophils, and hemoglobin(Approximately 27 months (end of study))
- Determine single and multiple dose pharmacokinetics (PK) profiles(Approximately 12 months)
- Number of participants with adverse events/serious adverse events(Approximately 27 months (end of study))
- Proportion of patients achieving ≥ 35% reduction in spleen volume by magnetic resonance imaging (MRI) at Week 24(24 weeks)
- Change in spleen volume as measured by MRI from baseline(Approximately 27 months (end of study))
研究者
研究点 (1)
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