John Mascarenhas, MD of the Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute speaks about the ASH 2020 Abstract – 55 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 protein family of bromodomain and extraterminal domain (BET) binds to chromatin to guide the transcription of target genes involved in multiple pro-fibrotic pathways and is a novel therapeutic target for myelofibrosis fibrosis reduction (MF). CPI-0610 is a distinctive, first-in-class, oral small-molecule BET (BETi) protein inhibitor designed to promote disease-modifying activity through selective gene regulation of key oncogenic, fibrotic, and inflammatory factors that can turn the standard of care in MF. Currently, CPI-0610 in combination with ruxolitinib (CPI-0610 +rux) is being tested in patients with JAK-inhibitor (JAKi) treatment-naïve MF (pts) in Arm 3 of MANIFEST, a Phase 2 national open-label trial. At 6-12 months, a minority of MF patients treated with rux (35 percent; 106 of 301) or fedratinib (37 percent; 35 of 96) achieved a reduction in spleen volume by 35 percent (SVR35). To improve outcomes in MF pts, disease-modifying therapeutic agents are required. The safety and efficacy data from Arm 3 of the ongoing MANIFEST study is recorded here.
Registration:
JAKi-treatment-naïve MF pts with DIPSS score ⇠Int-2; platelet ⇠100 x 109/L; CT/MRI spleen volume ⇠450 cc; ⇠2 observable symptoms (score ⇠3) or ⇠10 total symptom score (TSS) with MFSAF v4.0.0. Primary endpoint: SVR35 response at wk 24 (about 35 percent decrease in spleen volume); main secondary endpoint: TSS50 response at wk 24 (about 50 percent decrease in TSS); other endpoints: protection, PK, changes in proinflammatory cytokines and morphology/fibrosis of bone marrow
64 pts processed, 57 pts pending, as of 17 Apr 2020. Baseline characteristics: mean age: 67.1 years (yo) (SD: 10.27); 70.3 percent male; primary MF: 51.6 percent pts; DIPSS ⇠Int-2: 75.0 percent pts; 64.1 percent anemic pts (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 percent pts; JAK2 mutation: 71.9 percent pts; median TSS: 15.5 (range: 0, 38.3); high molecular risk mutations: 53.1 percent pts; JAK2 mutation: 71.9 percent pts; Median dose of Rux: 10 mg BID; median dose of CPI-0610: 125 mg QD. For SVR35 at wk 24, 30 pts is evaluable, including 28 pts earned ⇠24 wks of treatment and 2 pts discontinued prior to wk 24. SVR35 at wk 24 reached 63.3 percent (19/30) pts (median change -52.9 percent ; range: -84.4 percent , 23.7 percent ). 29 pts were assessable at wk 24 for TSS50 (1 pt missing baseline evaluation); 58.6 percent (17/29) pts reached TSS50 at wk 24 (1 pt missing baseline evaluation) (median change -64 percent ; range: -100 percent , 24.2 percent ). There was no effect on the efficacy outcome of the difference in baseline disease characteristics as no association was observed between spleen volume response at 24 wk and baseline spleen volume or baseline platelet count.
For protection, 64 pts are evaluable. There was a median exposure of 24.1 wks. Anemia (23.4 percent, ⇠Gr3: 17.2 percent) and thrombocytopenia (20.3 percent, ⇠Gr3: 4.7 percent) were the most common hematological treatment-emergent adverse events (TEAEs) of any grade. These cytopenias, including reductions/interruptions, were usually manageable with dosage modifications. Diarrhea (26.6 percent, no ⇠Gr3), respiratory tract infections (18.8 percent, ⇠Gr3: 4.7 percent), nausea (18.8 percent, no ⇠Gr3), stomach pain (15.6 percent, no ⇠Gr3), dysgeusia (14.1 percent, no ⇠Gr3), exhaustion (12.5 percent, no ⇠Gr3), headache and back pain (10.9 percent each, no ⇠Gr3), were the most common non-hematological TEAEs. 2 pts of discontinued care due to TEAEs (infections not associated with CPI-0610); 1 of them died within 30 days of discontinuation of treatment. In order to undergo allogeneic stem cell transplantation after 24 wks of treatment 1 pt of research was discontinued.
In JAKi-treatment-naïve MF pts, the CPI-0610 + rux combination is usually well-tolerated. As demonstrated by higher SVR35 and TSS50 rates at wk 24 compared to historical data from pivotal Ph3 trials, the preliminary data indicate the potential for combination therapy to provide enhanced efficacy. Overall, the data shows that in JAKi-naïve MF pts, the addition of CPI-0610 to rux is potentially synergistic.