KRT-232 Versus Best Available Therapy for the Treatment of Subjects With Myelofibrosis Who Are Relapsed or Refractory to JAK Inhibitor Treatment

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (Post-PV-MF), Post-Essential Thrombocythemia MF (Post-ET-MF)

Intervention / Treatment
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* Drug: KRT-232
* Drug: Best Available Therapy (BAT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 ECOG ≤ 2 Exclusion Criteria: 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Cohort 1<br>KRT-232 120 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles) | Drug: KRT-232<br>* KRT-232, administered by mouth<br>|
| Experimental: Part A Cohort 2<br>KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles) | Drug: KRT-232<br>* KRT-232, administered by mouth<br>|
| Experimental: Part A Cohort 3<br>KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles) | Drug: KRT-232<br>* KRT-232, administered by mouth<br>|
| Experimental: Part A Cohort 4b<br>KRT-232 240 mg by mouth once daily for Days 1-5, off treatment for Days 6-28 (28-day cycles) | Drug: KRT-232<br>* KRT-232, administered by mouth<br>|
| Experimental: Part B Arm 1 KRT-232<br>KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles) | Drug: KRT-232<br>* KRT-232, administered by mouth<br>|
| Active Comparator: Part B Arm 2 Best Available Therapy<br>Best available therapy at the discretion of the investigator, on a 28-day cycle. | Drug: Best Available Therapy (BAT)<br>* Best available therapy options include: hydroxyurea chemotherapy or supportive care (including but not limited to corticosteroids and androgens; JAK inhibitors not allowed).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Part A Only) Spleen Volume Reduction (SVR) | 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 | 24 weeks | 
| (Part B Only) Spleen Volume Reduction (SVR) | The proportion of subjects achieving SVR of ≥ 35% at Week 24 by MRI/CT scan (central review) | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Part A only) Improvement in Total Symptom Score (TSS) | The proportion of subjects 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 | 48 weeks | 
| (Part B only) Improvement of Total Symptom Score (TSS) | The proportion of subjects who have at least a 50% reduction from Baseline to Week 24 in the total symptom score as measured by the MF-SAF v4.0 | 24 Weeks | 
| (Part B only) Overall Survival (OS) | Time from randomization to death from any cause | 48 months | 
| (Part B only) Progression free survival (PFS) | Time from randomization to either first occurrence of disease progression or death due to any cause | 48 months | 
| (Part B Only) Overall Spleen Volume Reduction (SVR) | The proportion of subjects in each arm achieving SVR of ≥ 35% at any time by MRI/CT scan (central review) | 48 months | 
| (Part B Only) Spleen Response Duration | Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression | 48 months | 
| (Part B Only) Rate of conversion from RBC transfusion dependent to independent | The proportion of subjects who have RBC transfusion independence at week 24 | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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navtemadlin