Primary Myelofibrosis (PMF), Post-Polycythemia Vera MF (Post-PV-MF), Post-Essential Thrombocythemia MF (Post-ET-MF)
Conditions
Keywords
navtemadlin
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.
Interventions
DRUGKRT-232
KRT-232, administered by mouth
Best available therapy options include: 1. hydroxyurea 2. chemotherapy or 3. supportive care (including but not limited to corticosteroids and androgens; JAK inhibitors not allowed).
Sponsors
Kartos Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| (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
| Measure | Time frame | Description |
|---|---|---|
| (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 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) 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 |
| (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) 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 |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Croatia, Czechia, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Lithuania, Mexico, Philippines, Poland, Portugal, Romania, Russia, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Contacts
Primary ContactJohn Mei
Backup ContactYulia Khalina
Outcome results
None listed