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CPI-0610, a bromodomain and extraterminal domain protein (bet) inhibitor, in combination with ruxolitinib, in jak-inhibitor-naive myelofibrosis patients: update of manifest phase 2 study

Mead, A.
; 
Mascarenhas, J.
; 
Talpaz, M.
; 
Patriarca, A.
; 
Devos, T.
; 
Palandri, F.
; 
Passamonti, F.
; 
Rampal, R.
; 
Kremyanskaya, M.
; 
Scandura, J.
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Abstract
CPI-0610, a first-in-class, oral, small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins, potentially promotes disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors and CPI-0610, a first-in-class, oral, small-molecule inhibitor of bromodomain and extraterminal domain (BET) proteins, potentially promotes disease-modifying activity through altered gene regulation of key oncogenic, fibrotic, and inflammatory factors and may transform the standard of care in myelofibrosis (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. Approximately one third of JAKi naïve 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. CPI-0610, a potential disease- modifying therapeutic agent with a novel mechanism of action may improve the outcome 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 9 109/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 week 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 29 September 2020, 78 pts treated, 66 pts ongoing. Baseline characteristics: mean age: 67 years old; 72% male; primary MF: 54% pts; DIPSS ≥Int-2: 76% pts; IPSS ≥Int-2: 83%; 65% pts anemic (Hgb may transform the standard of care in myelofibrosis (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. Approximately one third of JAKi naïve 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. CPI-0610, a potential disease- modifying therapeutic agent with a novel mechanism of action may improve the outcome 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 9 109/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 week 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 29 September 2020, 78 pts treated, 66 pts ongoing. Baseline characteristics: mean age: 67 years old; 72% male; primary MF: 54% pts; DIPSS ≥Int-2: 76% pts; IPSS ≥Int-2: 83%; 65% pts anemic (Hgb <10 g/dl); median platelet: 294 9 109/L (range: 100, 1849); median spleen volume: 1719 cc (range: 451, 4782); median TSS: 16 (range: 0, 38); high-molecular-risk mutations: 55% pts, and JAK2 mutation: 72%. At week 24, 67% (42/63) pts achieved SVR35 (median % change from baseline: 50%; range: 84.4%, 23.7%) and 57% (34/ 60) pts achieved TSS50 (median % change from baseline: 59%; range: 100%, 225%). Additionally, 33% (16/48) of pts had at least one grade improvement in bone marrow fibrosis. 78 pts were evaluable for safety. Median exposure was 40 wks. The most common hematological treatment-emergent adverse events (TEAEs) of any grade were anemia (33%, ≥Gr3: 30%) and thrombocytopenia (32%, ≥Gr3: 8%). These cytopenias were generally manageable with dose modifications. The most common non-hematological TEAEs were diarrhea (30%, no ≥Gr3), dysgeusia (19%, no ≥Gr3), asthenic conditions (19%, no ≥Gr3), musculoskeletal pain (19%, no ≥Gr3), respiratory tract infections (18%, ≥Gr3: 1%), nausea (17%, no ≥Gr3), abdominal pain (17%, no ≥Gr3), and dizziness (17%, no ≥Gr3). CPI-0610 + rux combination is generally well-tolerated in JAKitreatment- naïve MF pts. The encouraging clinical 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 phase 3 studies. Overall, the data suggest that the addition of CPI-0610 to rux is potentially synergistic in JAKi-naïve MF pts. A phase 3, randomized, double blind, active-control study to further evaluate this combination is initiated
Authors
Mead, A.
Mascarenhas, J.
Talpaz, M.
Patriarca, A.
Devos, T.
Palandri, F.
Passamonti, F.
Rampal, R.
Kremyanskaya, M.
Scandura, J.
Somervaille, Tim CP
Wondergem, M.
Granacher, N.
Hoffman, R.
Gupta, V.
Luptakova, K.
Wang, J.
Christo, J.
Colak, G.
Shao, J.
Bobba, S.
Trojer, P.
Verstovsek, S
Harrison, C.
Affiliation
Oxford University Hospitals NHS Foundation Trust, Oxford,
Description
Date
2021
Publisher
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All Christie Publications
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Keywords
Type
Meetings and Proceedings
Citation
Mead A, Mascarenhas J, Kremyanskaya M, Hoffman R, Talpaz M, Patriarca A, et al. CPI-0610, A BROMODOMAIN and EXTRATERMINAL DOMAIN PROTEIN (BET) INHIBITOR, in COMBINATION with RUXOLITINIB, in JAK-INHIBITOR-NA VE MYELOFIBROSIS PATIENTS: UPDATE of MANIFEST PHASE 2 STUDY. British Journal of Haematology. 2021;193:96.
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Volume Title
URI
http://hdl.handle.net/10541/624073
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