KRT-232 Versus Best Available Therapy for the Treatment of Subjects With Myelofibrosis Who Are Relapsed or Refractory to JAK Inhibitor Treatment
- Conditions
- Primary Myelofibrosis (PMF)Post-Polycythemia Vera MF (Post-PV-MF)Post-Essential Thrombocythemia MF (Post-ET-MF)
- Interventions
- Drug: Best Available Therapy (BAT)
- Registration Number
- NCT03662126
- Lead Sponsor
- Kartos Therapeutics, Inc.
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 385
- 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
- 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Part A Cohort 3 KRT-232 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 KRT-232 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 KRT-232 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 Best Available Therapy (BAT) Best available therapy at the discretion of the investigator, on a 28-day cycle. Part A Cohort 1 KRT-232 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 KRT-232 KRT-232 240 mg by mouth once daily for Days 1-7, off treatment for Days 8-21 (21-day cycles)
- Primary Outcome Measures
Name Time Method (Part A Only) Spleen Volume Reduction (SVR) 24 weeks 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
(Part B Only) Spleen Volume Reduction (SVR) 24 Weeks The proportion of subjects achieving SVR of ≥ 35% at Week 24 by MRI/CT scan (central review)
- Secondary Outcome Measures
Name Time Method (Part A only) Improvement in Total Symptom Score (TSS) 48 weeks 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
(Part B only) Improvement of Total Symptom Score (TSS) 24 Weeks 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
(Part B Only) Overall Spleen Volume Reduction (SVR) 48 months The proportion of subjects in each arm achieving SVR of ≥ 35% at any time by MRI/CT scan (central review)
(Part B only) Overall Survival (OS) 48 months Time from randomization to death from any cause
(Part B only) Progression free survival (PFS) 48 months Time from randomization to either first occurrence of disease progression or death due to any cause
(Part B Only) Spleen Response Duration 48 months Time from initial SVR of ≥ 35% by MRI/CT (central review) until the first occurrence of disease progression
(Part B Only) Rate of conversion from RBC transfusion dependent to independent 24 weeks The proportion of subjects who have RBC transfusion independence at week 24
Trial Locations
- Locations (191)
The Kirklin Clinic of UAB Hospital
🇺🇸Birmingham, Alabama, United States
University of Southern California Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Stanford Cancer Center - Palo Alto
🇺🇸Stanford, California, United States
Innovative Clinical Research Institute
🇺🇸Whittier, California, United States
University Cancer Institute
🇺🇸Boynton Beach, Florida, United States
Northwestern University Feinberg School of Medicine
🇺🇸Chicago, Illinois, United States
University of Illinois at Chicago
🇺🇸Chicago, Illinois, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Brookdale University Hospital and Medical Center
🇺🇸Brooklyn, New York, United States
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