A Phase 2/3 Randomized, Controlled, Open-Label Study of KRT 232 in Subjects With Primary Myelofibrosis (PMF), Post Polycythemia Vera MF (Post-PV-MF), Or Post Essential Thrombocythemia MF (Post-ET-MF) Who Are Relapsed or Refractory to Janus Kinase (JAK) Inhibitor Treatment
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 385
- 试验地点
- 191
- 主要终点
- (Part A Only) Spleen Volume Reduction (SVR)
研究概览
简要总结
This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with myelofibrosis (MF) who no longer benefit from treatment with a JAK inhibitor. Inhibition of MDM2 is a novel mechanism of action in MF.
This study will be conducted in 2 phases. Phase 2 will determine the KRT-232 recommended dose and dosing schedule; Phase 3 will test KRT-232 vs Best Available Therapy (BAT). Patients in the Phase 3 part of the study will be randomized 2:1 to receive either KRT-232 (Arm 1) or BAT (Arm 2). The BAT administered will be determined by the treating physician, with the option to "cross-over" to KRT-232 treatment after 6 months of BAT or if the disease worsens at any time.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
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
- •Confirmed diagnosis of PMF, post-PV MF or post-ET MF (WHO)
- •High, intermediate-2, or intermediate-1 risk Dynamic International Prognostic System (DIPSS)
- •Failure of prior treatment with JAK inhibitor
排除标准
- •Prior splenectomy
- •Splenic irradiation within 3 months prior to randomization
- •History of major hemorrhage or intracranial hemorrhage within 6 months prior to randomization
- •History of stroke, reversible ischemic neurological defect or transient ischemic attack within 6 months prior to randomization
- •Prior MDM2 inhibitor therapy or p53-directed therapy
- •Prior allogeneic stem-cell transplant or plans for allogeneic stem cell transplant
- •History of major organ transplant
- •Grade 2 or higher QTc prolongation (> 480 milliseconds per NCI-CTCAE criteria, version 5.0)
研究组 & 干预措施
Part A Cohort 1
KRT-232 120 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
干预措施: KRT-232 (Drug)
Part A Cohort 2
KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
干预措施: KRT-232 (Drug)
Part A Cohort 3
KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)
干预措施: KRT-232 (Drug)
Part A Cohort 4b
KRT-232 240 mg by mouth once daily for Days 1-5, off treatment for Days 6-28 (28-day cycles)
干预措施: KRT-232 (Drug)
Part B Arm 1 KRT-232
KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)
干预措施: KRT-232 (Drug)
Part B Arm 2 Best Available Therapy
Best available therapy at the discretion of the investigator, on a 28-day cycle.
干预措施: Best Available Therapy (BAT) (Drug)
结局指标
主要结局
(Part A Only) Spleen Volume Reduction (SVR)
时间窗: 24 weeks
The proportion of subjects achieving a ≥ 35% spleen volume reduction (SVR) from Baseline to Week 24, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) scan
(Part B Only) Spleen Volume Reduction (SVR)
时间窗: 24 Weeks
The proportion of subjects achieving SVR of ≥ 35% at Week 24 by MRI/CT scan (central review)
次要结局
- (Part A only) Improvement in Total Symptom Score (TSS)(48 weeks)
- (Part B only) Improvement of Total Symptom Score (TSS)(24 Weeks)
- (Part B Only) Overall Spleen Volume Reduction (SVR)(48 months)
- (Part B only) Overall Survival (OS)(48 months)
- (Part B only) Progression free survival (PFS)(48 months)
- (Part B Only) Spleen Response Duration(48 months)
- (Part B Only) Rate of conversion from RBC transfusion dependent to independent(24 weeks)