CPI-0610, bromodomain and extraterminal domain protein (BET) inhibitor, as 'add-on' to ruxolitinib, in advanced myelofibrosis patients with suboptimal response: update of MANIFEST phase 2 study
Somervaille, Tim CP Verstovsek, S. Mascarenhas, J. Kremyanskaya, M. Hoffman, R. Rampal, R. Gupta, V. Talpaz, M. Granacher, N. Leber, B.
Somervaille, Tim CP
Verstovsek, S.
Mascarenhas, J.
Kremyanskaya, M.
Hoffman, R.
Rampal, R.
Gupta, V.
Talpaz, M.
Granacher, N.
Leber, B.
Citations
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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 may
transform the standard of care in myelofibrosis (MF). The majority of
MF patients (pts) show suboptimal responses to ruxolitinib (rux). In
addition, ≥Gr3 anemia (45.2%) and thrombocytopenia (12.9%) are AEs
associated with rux treatment. CPI-0610 may act synergistically in combination
with rux in advanced MF. Here we present results from Arm 2
of the ongoing Phase 2 MANIFEST study, investigating CPI-0610 as
“add-on” to rux in advanced MF pts with suboptimal response to rux.
Pts are stratified as transfusion dependent (TD, defined as ≥2U
RBCs/month over 12 weeks), and non-transfusion dependent (non-
TD). Eligibility: MF pts having a suboptimal or lost response to rux;
DIPSS ≥Int-2; platelets ≥75 x 109/L; ≥2 symptoms measurable (score
≥1) per MFSAF v4.0; RBC TD (TD cohort) or spleen volume of
≥450 cc by CT/MRI (non-TD cohort). Pts treated with rux for ≥6
months and on a stable dose for ≥8 weeks prior to enrollment. Rux
dose escalation is not allowed during the study. Primary endpoints:
TD cohort: TD to TI (transfusion independence) [defined as no
transfusion for 12 weeks per IWG-MRT criteria]; non-TD cohort:
SVR35 response (≥35% spleen volume reduction) at week 24. Secondary
endpoints: TSS50 response (≥50% total symptom score
reduction) per MFSAF v4.0 at wk 24, safety and PK.
As of 29 Sep 2020, 52 pts were treated in the TD cohort (median
treatment duration 30 weeks, range: 1, 166 weeks). Mean age 70 years,
67% male, 94% with hemoglobin (Hgb) <10 g/dL, 100% with DIPSS
≥Int-2, 79% with primary MF, 56% with high-molecular-risk and 52%
with JAK2 mutations. 36% (13/36) of TD pts converted to TI. At wk 24,
21% (7/33) pts achieved SVR35 (median % change from baseline: 19%, range: 54%, 48%), and 46% (15/33) pts achieved TSS50 (median
% change from baseline: -58%, range: -100%, 24%).
In non-TD cohort, 26 pts were treated (median treatment duration
51 weeks, range: 2, 111 weeks). Mean age 63 years (SD: 7), 50%
male, 73% with DIPSS ≥Int-2, 54% with primary MF, 77% with
high-molecular-risk and 81% with JAK2 mutations. At week 24, 29%
(6/21) pts achieved SVR35 (median % change from baseline: 17%,
range: 90%, 16%), and 38% (8/21) pts achieved TSS50 (median %
change from baseline: 45%, range: 100%, 22%).
78 pts were evaluable for safety across the TD and non-TD
cohorts. Median exposure was 45 weeks. The most common hematological
treatment-emergent adverse events (TEAEs) of any grade were
thrombocytopenia (45%, ≥Gr3: 23%) and anemia (14%, ≥Gr3:
10%). The most common (≥20%) non-hematological TEAEs were
diarrhea (51%, ≥Gr3: 4%), respiratory tract infections (35%, ≥Gr3:
5%), asthenic conditions (33%, ≥Gr3: 4%), nausea (33%, Brentuximab vedotin plus chemotherapy for patients with previously untreated, Stage III or IV classical Hodgkin lymphoma: 5-year update of the phase 3 ECHELON-1 studyGr3: 3%),
cough (24%, no ≥Gr3) and dysgeusia (22%, no ≥Gr3). 9 pts (12%)
discontinued treatment due to TEAEs.
Early clinical data indicate that CPI-0610 as “add-on” to rux is
generally well tolerated. The combination therapy provided clinical
benefits in most pts as assessed by SVR, and symptomatic responses.
In addition, conversion to TI was also observed in TD patients.
Authors
Somervaille, Tim CP
Verstovsek, S.
Mascarenhas, J.
Kremyanskaya, M.
Hoffman, R.
Rampal, R.
Gupta, V.
Talpaz, M.
Granacher, N.
Leber, B.
Kiladjian, J. J.
Vannucchi, A.
Bose, P.
McMullin, M.
Sirhan, S.
Ribrag, V.
Prejzner, W.
Foltz, L.
Patriarca, A.
Lambert, J.
Luptakova, K.
Christo, J.
Wang, J.
Colak, G.
Shao, J.
Bobba, S.
Trojer, P
Harrison, C.
Verstovsek, S.
Mascarenhas, J.
Kremyanskaya, M.
Hoffman, R.
Rampal, R.
Gupta, V.
Talpaz, M.
Granacher, N.
Leber, B.
Kiladjian, J. J.
Vannucchi, A.
Bose, P.
McMullin, M.
Sirhan, S.
Ribrag, V.
Prejzner, W.
Foltz, L.
Patriarca, A.
Lambert, J.
Luptakova, K.
Christo, J.
Wang, J.
Colak, G.
Shao, J.
Bobba, S.
Trojer, P
Harrison, C.
Description
Date
2021
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Somervaille T, Verstovsek S, Bose P, Mascarenhas J, Kremyanskaya M, Hoffman R, et al. CPI-0610, bromodomain and extraterminal domain protein (BET) inhibitor, as add-on to ruxolitinib, in advanced myelofibrosis patients with suboptimal response: Update of MANIFEST phase 2 study. British Journal of Haematology. 2021;193:98-99.