BOREAS: A Global Phase 3 Study of KRT-232, a First-in-class Murine Double Minute 2 (MDM2) Inhibitor in TP53WT Relapsed/refractory (R/R) Myelofibrosis (MF).

TPS7057 Background: The prognosis for patients (pts) with MF who have primary resistance to or who have progressed after treatment with ruxolitinib (RUX) is poor (median OS is ̃13 months), highlighting the unmet need for novel treatments in this setting. MDM2 is a key negative regulator of the tumor suppressor protein p53 that is overexpressed in CD34+ cells in MF pts. Elevated MDM2 expression attenuates p53 activity, resulting in proliferation of malignant CD34+ cells. KRT-232 is a potent, selective, orally available MDM2 inhibitor that restores p53 function resulting in apoptosis of malignant stem and progenitor cells. KRT-232 has the potential to demonstrate disease-modifying effects in MF pts who are R/R to prior JAK inhibitor (JAKi) therapy. The FDA has granted KRT-232 Fast Track designation for the treatment of JAKi R/R MF. Clinical proof-of-concept for KRT-232 in R/R MF was established in phase 2 of this study. Once-daily dosing of KRT-232 at 240 mg (Day 1-7 of 28-day cycle) yielded a best spleen volume reduction (SVR) ≥35% by central review in 16% of pts, best total symptom score (TSS) response > 50% in 30% of pts, and 87% reduction of CD34+ cells in peripheral blood at Week 24. Spleen responses were superior in pts who were off RUX vs those on RUX at baseline imaging (best SVR ≥35%: 29% vs 0%). KRT-232 demonstrated a tolerable safety profile that included prophylaxis for nausea/vomiting (Al-Ali. EHA 2020). Methods: BOREAS is a randomized, controlled, open-label, global phase 3 study in MF pts (primary MF/post–polycythemia vera MF/post–essential thrombocythemia MF) who are R/R to JAKi. Pts aged ≥18 y with confirmed MF per WHO criteria, intermediate-1, 2, or high-risk disease (per DIPSS), ECOG performance status ≤2, adequate hematologic function (platelets ≥50 x 109/L), and wild-type p53 will be enrolled; pts with JAKi treatment = 28 d before baseline MRI/CT will be excluded. Pts will be randomized (2:1) to KRT-232 (240 mg on Day 1-7/28-day cycle; n = 188) or best available treatment (BAT; n = 94) and stratified by MF type (primary vs secondary) and baseline TSS (≤10 vs > 10). BAT options include hydroxyurea, chemotherapy, or supportive care (including; but not limited to: corticosteroids and androgens); treatment selection is at the discretion of the investigator. Pts in BAT arm with documented disease progression at any time (spleen volume increase ≥25% from baseline or confirmed leukemic transformation) or those who complete Week 24 assessments may crossover to the KRT-232 arm. Primary endpoint is rate of SVR ≥35% by MRI/CT at Week 24 (central review). Key secondary endpoints are ≥50% reduction in TSS rate at Week 24 (per MFSAF v4.0), PFS, OS, best overall SVR ≥35%, and duration of spleen response. Enrollment is planned at 137 sites in 21 countries in North and South America, Europe, and Asia-Pacific (ClinicalTrials.gov: NCT03662126). Clinical trial information: NCT03662126.