Abstract
<h3>Context:</h3> CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET proteins, designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors with potential to transform the standard of care in MF. JAKi are currently approved for treatment of MF, including ruxolitinib (rux) and fedratinib. Approximately one-third of JAKi-naïve MF pts treated with rux (35%; 106 of 301) or fedratinib (37%; 35 of 96) achieved a spleen volume reduction ≥35% (SVR35) at 6–12 months. CPI-0610, a potential disease-modifying therapeutic agent with a novel MoA may improve the outcome in MF pts. Clinical activity of CPI-0610 in combination with rux in JAKi-naïve MF pts observed in the phase 2 MANIFEST study was higher than with rux alone in historical phase 3 trials. <h3>Design:</h3> MANIFEST-2 is a global, phase 3, 1:1 randomized, double-blind, active-control study of CPI-0610 + rux <i>vs</i> placebo + rux in JAKi treatment-naïve patients with primary MF, post-polycythemia-vera MF, or post-essential-thrombocythemia MF. <h3>Patients:</h3> Key eligibility criteria: DIPSS score ≥Int-1; platelet ≥ 100 x 10<sup>9</sup>/L; spleen volume ≥ 450 cc by CT/MRI; ≥ 2 symptoms measurable (score ≥3) or a total symptom score (TSS) of ≥ 10 using the MFSAF v4.0; peripheral blast count <5%, ECOG ≤2. Approximately 310 patients (155 in each arm) will be enrolled in the study. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 <i>vs</i> Intermediate-2 <i>vs</i> High), platelet count (≥ 200 × 10<sup>9</sup>/L <i>vs</i> 100–200 × 10<sup>9</sup>/L), and spleen volume (≥ 1800 cm<sup>3</sup> <i>vs</i> < 1800 cm<sup>3</sup>). <h3>Interventions:</h3> Double-blind treatment (CPI-0610 or matching placebo) will be administered QD for 14 consecutive days followed by a 7-day break, which is considered 1 cycle of treatment. Rux will be administered BID for all 21 days within each cycle. <h3>Main Outcomes Measures:</h3> Primary endpoint: SVR35 response at wk 24; key secondary endpoint: TSS50 response (≥50% reduction in TSS) at wk 24; other secondary endpoints: safety, PK, PD, bone marrow morphology/fibrosis, duration of SVR35 response, duration of TSS50 response, PFS, OS, conversion from transfusion dependence to independence, rate of RBC transfusion for the first 24 wks, hemoglobin response, and peripheral proinflammatory cytokines.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call