KRT-232 Compared to Ruxolitinib in Patients With Phlebotomy-Dependent Polycythemia Vera

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 phlebotomy-dependent polycythemia vera (PV). Inhibition of MDM2 in PV is a new mechanism of action in PV. In Part A, patients must be resistant or intolerant to hydroxyurea or have undergone treatment with interferon. In Part B, patients must be resistant or intolerant to hydroxyurea. This study is a global, open-label Phase 2a/2b study to determine the efficacy and safety of KRT-232. In Part A of the study, patients will be randomly assigned to 5 arms with 2 different doses and 3 different dosing schedules of KRT 232. In Part B of the study, patients will be randomized either to treatment with KRT-232 administered at the recommended dose and schedule from Part A or to treatment with ruxolitinib.

Official Title
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A Two-Part, Randomized, Open-label, Multicenter, Phase 2a/2b Study of the Efficacy, Safety, and Pharmacokinetics of KRT-232 Compared to Ruxolitinib in Patients With Phlebotomy-Dependent Polycythemia Vera

Conditions
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Polycythemia Vera

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 PV (WHO 2016) ECOG ≤ 2 Part A: patients with and without splenomegaly are eligible Part A: patients must be resistant or intolerant to hydroxyurea or have undergone treatment with interferon Part B: only patients with splenomegaly are eligible Part B: patients must be resistant or intolerant to hydroxyurea Exclusion Criteria: Diagnosis of post-PV myelofibrosis (IWG-MRT) Prior treatment with MDM2 inhibitors, p53-directed therapies, HDAC, BCL 2 inhibitors Splenic irradiation within 3 months prior to the first dose of study treatment Clinically significant thrombosis within 3 months of screening Grade 2 or higher QTc prolongation Part B: prior treatment with a JAK inhibitor

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Arm 1<br>KRT-232 120mg 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 Arm 2<br>KRT-232 240mg 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 Arm 3<br>KRT-232 120mg 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 B KRT-232 Arm<br>Recommended KRT-232 dose and schedule from Part A | Drug: KRT-232<br>* KRT-232, administered by mouth<br>|
| Active Comparator: Part B Ruxolitinib Arm<br>Ruxolitinib per approved prescribing label | Drug: Ruxolitinib<br>* Ruxolitinib per approved prescribing label<br>|
| Experimental: Part A Arm 4b<br>KRT-232 240mg 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 A Arm 2b<br>KRT-232 240mg 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>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with splenomegaly achieving a response at Week 32 | Response defined as having achieved both of the following: The absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32, with no more than one phlebotomy eligibility occurring post-randomization and prior to the Week 8 visit A reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 32 | 32 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response after achieving both the absence of phlebotomy eligibility and reduction in spleen volume (for patients with splenomegaly) |  | 4 years | 
| Duration of response after achieving phlebotomy independence |  | 4 years | 
| Change from baseline of MPN-SAF TSS v2.0 patient-reported outcome |  | 32 weeks | 
| Change from baseline of EORTC-QLQ-C30 patient-reported outcome |  | 32 weeks |