KRT-232-115

Adults with PMF/post-PV MF/post-ET MF, ECOG 0–2, TP53WT at randomization, ruxolitinib run-in response in suboptimal range, stable ruxolitinib dosing, protocol-defined hematologic/hepatic/renal function, and strict contraception requirements.

Ruxolitinib Run-in Period (core): 1. Primary MF (PMF), post-polycythemia vera MF (post-PV MF), or post-essential thrombocythemia MF (post-ET MF) requiring treatment and meeting protocol diagnostic criteria. 2. ECOG performance status 0-2. 3. Adequate baseline hematologic, hepatic, and renal function per protocol. 4. Contraception requirements for women/men of reproductive potential and partners, with post-treatment continuation windows per protocol. Randomized Period (must meet all at randomization): 1. PMF, post-PV MF, or post-ET MF that is TP53WT by central testing. 2. ECOG 0-2. 3. Ruxolitinib monotherapy for >=18 weeks but <25 weeks, with stable dose for the 8 consecutive weeks prior to randomized treatment. - Stable dose = no treatment holds or dose adjustments. - Must be stable at >=5 mg BID. 4. Suboptimal response to ruxolitinib run-in, defined as: - SVR >0% but <35%, and - TSS reduction >0% but <50%, assessed from run-in baseline to end of run-in. 5. Adequate organ function within 14 days before first randomized dose: a) Hematologic: - ANC >=1.5 x 10^9/L without myeloid growth factors during prior 28 days, - Platelets >=100 x 10^9/L. b) Hepatic: - Total bilirubin within normal limits, or if >ULN then direct bilirubin <=2 x ULN and total bilirubin <=3 x ULN. - AST/ALT <=2.5 x ULN. c) Renal: - Estimated creatinine clearance >=30 mL/min (Cockcroft-Gault). 6. Reproductive requirements: highly effective contraception during study and protocol-defined post-last-dose periods.

Prior JAK inhibitor or prohibited targeted therapies, prior splenectomy/recent splenic irradiation, high blast burden, active serious infection (including HIV/HBV/HCV criteria), major unstable cardiac/intercurrent disease, bleeding risk, significant QTc prolongation, recent major surgery/radiation, pregnancy/breastfeeding, and transplant-related restrictions.

Ruxolitinib Run-in exclusions include: 1. Recent participation in another interventional trial (observational allowed). 2. Prior JAK inhibitor therapy. 3. Prior BCL-XL/BET/MDM2/PI3K/PIM/XPO1 inhibitors or p53-directed therapy; insufficient washout of MF-directed drugs (with protocol exceptions for stable supportive meds). 4. Prior splenectomy. 5. Splenic irradiation within 3 months before run-in start. 6. Recent non-spleen-directed MF radiation, major surgery, or planned major surgery within 28 days before run-in start. 7. Prior allogeneic transplant or transplant eligibility (except eligible-but-refusing transplant is allowed per protocol). 8. Peripheral blood or marrow blasts >=10% within 28 days before first run-in dose. 9. Pregnancy or breastfeeding. 10. History of solid organ transplant. 11. HIV infection. 12. Active hepatitis B or C infection (per protocol table criteria). 13. Active serious viral/mycobacterial/parasitic/fungal/bacterial infection (including acute hepatitis A, herpes zoster, PML). 14. Uncontrolled intercurrent illness (including significant NYHA III/IV cardiac disease, unstable angina, symptomatic CHF, serious arrhythmia, severe psychiatric/social limitations). 15. Active/chronic bleeding within 28 days before run-in. 16. Active fever >38.2C within 14 days before run-in. 17. Other malignancy within 3 years except protocol-specified low-risk/treated exceptions. 18. Grade >=2 QTc prolongation (>480 msec). 19. Significant swallowing/malabsorption/chronic GI conditions likely to impair treatment adherence/absorption. 20. Severe hypersensitivity to navtemadlin/ruxolitinib/excipients or required prophylaxis. 21. Stroke/reversible ischemic neurologic defect/TIA within 6 months before run-in. 22. Indwelling surgical drains (e.g., peritoneal/CNS/pleural). 23. Symptomatic ascites requiring paracentesis. 24. Any open wound or ulcer. Randomized period additional exclusions include: - WBC dynamic criterion indicating marked increase and absolute high count, - Active prohibited targeted therapies, - Repeat of key infection/transplant/surgery/blast burden/pregnancy and severe comorbidity exclusions, - Any concurrent condition making patient unsuitable per investigator.