Description:
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.
Title
- Brief Title: KRT-232 Versus Best Available Therapy for the Treatment of Subjects With Myelofibrosis Who Are Relapsed or Refractory to JAK Inhibitor Treatment
- Official Title: 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
Clinical Trial IDs
- ORG STUDY ID:
KRT-232-101
- NCT ID:
NCT03662126
Conditions
- Primary Myelofibrosis (PMF)
- Post-Polycythemia Vera MF (Post-PV-MF)
- Post-Essential Thrombocythemia MF (Post-ET-MF)
Interventions
| Drug | Synonyms | Arms |
|---|
| KRT-232 | | Part A Cohort 1 |
| Best Available Therapy (BAT) | | Part B Arm 2 Best Available Therapy |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Part A Cohort 1 | Experimental | KRT-232 120 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles) | |
| Part A Cohort 2 | Experimental | KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles) | |
| Part A Cohort 3 | Experimental | KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles) | |
| Part A Cohort 4b | Experimental | KRT-232 240 mg by mouth once daily for Days 1-5, off treatment for Days 6-28 (28-day cycles) | |
| Part B Arm 1 KRT-232 | Experimental | KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-28 (28-day cycles) | |
| Part B Arm 2 Best Available Therapy | Active Comparator | Best available therapy at the discretion of the investigator, on a 28-day cycle. | - Best Available Therapy (BAT)
|
Eligibility Criteria
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 randomizatio
- 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)
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | (Part A Only) Spleen Volume Reduction (SVR) |
| Time Frame: | 24 weeks |
| Safety Issue: | |
| Description: | 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 |
Secondary Outcome Measures
| Measure: | (Part A only) Improvement in Total Symptom Score (TSS) |
| Time Frame: | 48 weeks |
| Safety Issue: | |
| Description: | 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 |
| Measure: | (Part B only) Improvement of Total Symptom Score (TSS) |
| Time Frame: | 24 Weeks |
| Safety Issue: | |
| Description: | 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 |
| Measure: | (Part B only) Overall Survival (OS) |
| Time Frame: | 48 months |
| Safety Issue: | |
| Description: | Time from randomization to death from any cause |
| Measure: | (Part B only) Progression free survival (PFS) |
| Time Frame: | 48 months |
| Safety Issue: | |
| Description: | Time from randomization to either first occurrence of disease progression or death due to any cause |
| Measure: | (Part B Only) Overall Spleen Volume Reduction (SVR) |
| Time Frame: | 48 months |
| Safety Issue: | |
| Description: | The proportion of subjects in each arm achieving SVR of ≥ 35% at any time by MRI/CT scan (central review) |
| Measure: | (Part B Only) Spleen Response Duration |
| Time Frame: | 48 months |
| Safety Issue: | |
| Description: | Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression |
| Measure: | (Part B Only) Rate of conversion from RBC transfusion dependent to independent |
| Time Frame: | 24 weeks |
| Safety Issue: | |
| Description: | The proportion of subjects who have RBC transfusion independence at week 24 |
Details
| Phase: | Phase 2/Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Kartos Therapeutics, Inc. |
Trial Keywords
Last Updated
August 5, 2021
