Schéma : 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 JAK inhibitor. Inhibition of MDM2 is a novel mechanism of action in MF.

This study is a global, open-label Phase 2 study to determine the efficacy and safety of KRT-232 in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF who have failed previous treatment with JAK inhibitor (Part A), or Ruxolitinib (Part B). In Part A of the study, patients will be randomly assigned to 2 different doses and 2 different dosing schedules of KRT-232. In Part B of the study, patients will be treated at the recommended dose and schedule from Part A.

Study arms:
- Experimental: Part A Cohort 1
KRT-232 120mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
Intervention: Drug: KRT-232

- Experimental: Part A Cohort 2
KRT-232 240mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
Intervention: Drug: KRT-232

- Experimental: Part A Cohort 3
KRT-232 240mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles)
Intervention: Drug: KRT-232

- Experimental: Part B
Recommended KRT-232 dose and schedule from Part A
Intervention: Drug: KRT-232

Current primary outcome:
To determine spleen response [ Time Frame: 24 weeks ]. The proportion of patients achieving a ≥ 35% spleen volume reduction from Baseline to Week 24, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) scan

Current secondary outcomes:
- To determine the change in modified MPN-SAF Total Symptom Score (TSS) at Week 24 and Week 48 [ Time Frame: 48 weeks ]
Proportion of patients who have at least a 50% reduction from Baseline to Week 24 and Week 48 in the total symptom score as measured by the modified MPN-SAF v2.0
- RBC transfusion independence at Week 24 [ Time Frame: 24 weeks ]
Proportion of patients who have RBC transfusion independence at week 24
- Complete remission and partial remission defined according to International Working Group-Myeloproliferative Neoplasms Research and Treatment and modified European LeukemiaNet criteria [ Time Frame: 24 weeks ]
Proportion of patients who have complete remission and partial remission at week 24