CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, in Combination with Ruxolitinib, in JAK-Inhibitor-Naïve Myelofibrosis Patients: Update of MANIFEST Phase 2 Study

The bromodomain and extraterminal domain (BET) family of proteins bind to chromatin to regulate the transcription of target genes involved in multiple pro-fibrotic pathways and is a novel therapeutic target for reducing fibrosis in myelofibrosis (MF). CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET (BETi) 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. CPI-0610 in combination with ruxolitinib (CPI-0610 +rux) is currently being studied in JAK-inhibitor (JAKi) treatment-naïve MF patients (pts) in Arm 3 of MANIFEST, a global, open-label, Phase 2 study. A minority of MF patients treated with rux (35%; 106 of 301) or fedratinib (37%; 35 of 96) achieved a spleen volume reduction ≥ 35% (SVR35) at 6-12 months. Disease-modifying therapeutic agents are needed to improve the outcomes in MF pts. Here we report the safety and efficacy data from Arm 3 of the ongoing MANIFEST study.

Eligibility: JAKi-treatment-naïve MF pts with DIPSS score ≥Int-2; platelet ≥100 x 10⁹/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. Primary endpoint: SVR35 response (≥35% reduction in spleen volume) at wk 24; key secondary endpoint: TSS50 response (≥50% reduction in TSS) at wk 24; other endpoints: safety, PK, changes in proinflammatory cytokines and bone marrow morphology/fibrosis

As of 17 Apr 2020, 64 pts treated, 57 pts ongoing. Baseline characteristics: mean age: 67.1 years old (yo) (SD: 10.27); 70.3% male; primary MF: 51.6% pts; DIPSS ≥Int-2: 75.0% pts; 64.1% pts anemic (Hgb <10g/dL); median platelet: 302 x 10⁹/L (range: 100, 1849); median spleen volume: 1770 cc (range: 457, 4782); median TSS: 15.5 (range: 0, 38.3); high-molecular-risk mutations: 53.1% pts, JAK2 mutation: 71.9%, CALR mutation: 21.9%, and MPL mutation: 4.7%. Median rux dose: 10 mg BID; median CPI-0610 dose: 125 mg QD. 30 pts were evaluable for SVR35 at wk 24, including 28 pts received ≥24 wks of treatment and 2 pts discontinued prior to wk 24. 63.3% (19/30) pts achieved SVR35 at wk 24 (median change -52.9%; range: -84.4%, 23.7%). 29 pts were evaluable for TSS50 at wk 24 (1 pt missing baseline evaluation); 58.6% (17/29) pts achieved TSS50 at wk 24 (median change -64%; range: -100%, 24.2%). The difference in baseline disease characteristics had no bearing on the efficacy outcome as there was no correlation observed between spleen volume response at 24 wk with baseline spleen volume or baseline platelet count.

64 pts were evaluable for safety. Median exposure was 24.1 wks. The most common hematological treatment-emergent adverse events (TEAEs) of any grade were anemia (23.4%, ≥Gr3: 17.2%) and thrombocytopenia (20.3%, ≥Gr3: 4.7%). These cytopenias were generally manageable with dose modifications, including reductions/interruptions. The most common non-hematological TEAEs were diarrhea (26.6%, no ≥Gr3), respiratory tract infections (18.8%, ≥Gr3: 4.7%), nausea (18.8%, no ≥Gr3), abdominal pain (15.6%, no ≥Gr3), dysgeusia (14.1%, no ≥Gr3), fatigue (12.5%, no ≥Gr3), headache and back pain (10.9% each, no ≥Gr3). 2 pts discontinued treatment due to TEAEs (infections unrelated to CPI-0610); 1 of them died within 30 days of treatment discontinuation. 1 pt discontinued study in order to undergo allogeneic stem cell transplantation after 24 wks of treatment.

CPI-0610 + rux combination is generally well-tolerated in JAKi-treatment-naïve MF pts. The preliminary data demonstrate the potential for the combination treatment to provide enhanced efficacy as evidenced by higher SVR35 and TSS50 rates at wk 24 compared with historical data from pivotal Ph3 studies. Overall, the data suggest that the addition of CPI-0610 to rux is potentially synergistic in JAKi-naïve MF pts.