Study of KRT-232 or TL-895 in Janus Associated Kinase Inhibitor Treatment-Naïve Myelofibrosis

Study Overview
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Brief Summary
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This study evaluates either KRT-232 or TL-895 in treatment naïve patients with myelofibrosis (MF) The study will be conducted in 2 stages. Stage 1 will evaluate safety, tolerability, and efficacy of either KRT-232 (Arm 1) or TL-895 (Arm 2) in treatment naïve patients. Stage 2 will expand enrollment in Arm 1 and/or Arm 2 if expansion criteria is met.

Official Title
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An Open-Label, Multicenter, Phase 2 Study Assessing the Safety and Efficacy of KRT-232 or TL-895 in Janus Associated Kinase Inhibitor Treatment-Naïve Myelofibrosis

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

Intervention / Treatment
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* Drug: KRT-232
* Drug: TL-895


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-risk, or intermediate-1 and 2 risk, defined by Dynamic International Prognostic System (DIPSS) ECOG of 0 or 1 Exclusion Criteria: Subjects who are positive for p53 mutation (Arm 1) Prior MDM2 inhibitor therapy or p53-directed therapy (Arm 1) Prior treatment with any JAK inhibitor Prior splenectomy Splenic irradiation within 24 weeks prior to randomization Prior allogeneic stem-cell transplantation or plans for allogeneic stem-cell transplant History of major organ transplant Grade 2 or higher QTc prolongation Major hemorrhage or intracranial hemorrhage within 24 weeks prior to randomization

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>KRT-232 administered orally as 240 mg once daily on Days 1-7, off treatment on Days 8-28, in 28-day treatment cycles | Drug: KRT-232<br>* KRT-232, administration by mouth<br>|
| Experimental: Arm 2<br>TL-895 administered orally as 150 mg twice daily continuously in 28-day cycles | Drug: TL-895<br>* TL-895, administration by mouth<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in 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 | 
| Spleen Response Duration | Time from initial SVR of ≥35% by MRI/CT (central review) until progression | 48 months | 
| Rate of conversion from RBC transfusion dependent to independent | The proportion of subjects who convert from transfusion dependent to transfusion independent at Week 24 | 24 weeks | 
| Overall Survival (OS) | Time from first dose to death from any cause | 48 months | 
| Progression free survival (PFS) | Time from randomization to either first occurrence of disease progression or death due to any cause | 48 months | 

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