An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 Combined With Ruxolitinib in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (Post-PV-MF), Or Post-Essential Thrombocythemia MF (Post ET-MF) Who Have a Suboptimal Response to Ruxolitinib

Study Overview
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Brief Summary
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This is a phase 1b/2 study of KRT-232 combined with ruxolitinib in subjects with MF who have a suboptimal response after at least 18 weeks of treatment with ruxolitinib. The primary objective of the study is to determine a recommended phase 2 dose (RP2D) of KRT 232 in combination with ruxolitinib.

Official Title
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An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 Combined With Ruxolitinib in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (Post-PV-MF), Or Post-Essential Thrombocythemia MF (Post ET-MF) Who Have a Suboptimal Response to Ruxolitinib

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: KRT-232
* Drug: Ruxolitinib


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, as assessed by treating physician according to the World Health Organization (WHO) Treatment with ruxolitinib for ≥18 weeks prior to study entry, and on a stable dose of ruxolitinib in the 8 weeks prior to study entry Spleen ≥5 cm palpable below the LLCM or ≥450 cm3 by MRI or CT Patients must have at least 2 symptoms with a score of at least 1 on the MFSAF v4.0 ECOG performance status of 0 to 2 Exclusion Criteria: Patients who are positive for TP53 mutations Documented disease progression or clinical deterioration any time while on ruxolitinib treatment Patients who have had a documented spleen response to ruxolitinib. Prior splenectomy Prior MDM2 inhibitor therapy or p53-directed therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, Arm 1, Cohort 1<br>KRT-232 by mouth once daily for Days 1-7, off treatment for Days 8-28 (28 day cycle) | Drug: KRT-232<br>* administered by mouth<br>Drug: Ruxolitinib<br>* administered by mouth<br>* Other names: Jakavi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For Phase 1: To determine the KRT-232 RP2D in combination with ruxolitinib | Dose limiting toxicities will be used to establish the MTD of KRT-232 in combination with ruxolitinib. Subsequently, RP2D will be based on safety and efficacy data of the combination. | 15 months | 
| For Phase 2:To determine the spleen volume reduction (SVR) at Week 24 | The proportion of subjects achieving SVR of ≥ 35% at Week 24 by MRI/CT scan | 6 months after last patient enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine spleen response | The proportion of subjects achieving ≥35% SVR at any time point from Baseline while on study, as assessed by MRI (or by CT scan for applicable subjects) | 43 months | 
| To determine the change in Total Symptom Score (TSS) based Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) | The percentage change in TSS as measured by the MFSAF v4.0 at any time point from Baseline while on study | 43 months | 

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