A Phase Ib/II, Open-label, Multi-center, Dose-finding Study to Assess the Safety and Efficacy of the Oral Combination of LDE225 and INC424 (Ruxolitinib) in Patients With Myelofibrosis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b)
研究概览
简要总结
The purpose of this phase Ib/II clinical trial was to: a) evaluate the safety of the co-administration of LDE225 and INC424 in myelofibrosis patients and establish a maximum tolerated dose and/or Recommended Phase II dose of the combination and b) to assess the efficacy of the co-administration of LDE225 and INC424 on spleen volume reduction.
详细描述
The study is considered to have been completed because the participants completed the study as per study design at the time of trial termination. If participants were already in extension phase until discontinuation criteria were met or alternative setting was available, they were considered as completed. The study was terminated due to one of the compounds being divested.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosed with PMF per 2008 WHO criteria, post-PV MF or post-ET MF per IWG-MRT criteria.
- •Ineligible or unwilling to undergo stem cell transplantion.
- •PLT counts > or = 75X 10^9/L not reached with the aid of transfusions.
- •ECOG performance status ≤
- •Palpable splenomegaly defined as ≥ 5 cm below the left costal margin.
- •Intermediate risk level 1 (1 prognostic factor which is not age), Intermediate risk level 2, or high risk.
- •Active symptoms of MF as demonstrated by one symptom score of at least 5 (0 to10 point scale) or two symptom scores of at least 3 (0 to 10 point scale) on the MF Symptom Assessment Form (MFSAF).
排除标准
- •Previous therapy with JAK or Smoothened inhibitors.
- •Patient is currently on medications that interfere with coagulation (including warfarin) or platelet function with the exception of low dose aspirin (up to 100 mg) and LMWH.
- •Impairment of GI function or GI disease that may significantly alter the absorption of INC424 or LDE225 (e.g., uncontrolled nausea, vomiting, diarrhea; malabsorption syndrome; small bowel resection).
- •Splenic irradiation within 12 months prior to Screening.
- •Pregnant or nursing women.
- •WOCBP not using highly effective methods of contraception
- •Sexually active males who refuse condom use
- •Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and gemfibrozil. Pravastatin may be used if necessary, with extra caution.
研究组 & 干预措施
LDE225 + INC424
LDE225 and INC424 in combination
干预措施: LDE225 (Drug)
LDE225 + INC424
LDE225 and INC424 in combination
干预措施: INC424 (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b)
时间窗: 6 weeks (42 days)
A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.
Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1
时间窗: Week 24 and Week 48
Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients
次要结局
- Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores(Week 24, Week 48)
- Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores(Baseline, Week 25, Week 49)
- Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h)(0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1)
- Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1(Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48))
- Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast(0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1)
- Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax)(0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1)
- Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax)(0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1)
- Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F)(0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1)
- Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1(Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48))
- Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers(Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48))
- Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48(Week 24, Week 48)
- Phase Ib and Phase II: LDE225: PK Parameter: Racc(0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 9 Day 1)
- Phase Ib and Phase II: INC424: PK Parameter: T1/2(0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1)
- Phase Ib and Phase II: INC424: PK Parameter: Vss/F(0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1)