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denotes that this is a ticketed session.Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical: New Therapies and JAKi-based Combinations for Myelofibrosis
Hematology Disease Topics & Pathways:
Diseases, MPN, Myeloid Malignancies
CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of bromodomain and extraterminal domain (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 myelofibrosis (MF). The majority of MF patients (pts) show suboptimal responses to ruxolitinib (rux), and there is limited evidence of disease modification. In addition, ≥Gr3 anemia (45.2%) and thrombocytopenia (12.9%) are concerns associated with rux treatment. The outcomes for pts who discontinue rux are poor, with median survival of approximately 1 year (Newberry et al. 2017; Mascarenhas et al. 2020). 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 wks, IWG-MRT criteria], 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 wks 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 wks per IWG-MRT criteria]; non-TD cohort: SVR35 response (≥35% spleen volume reduction) at wk 24. Secondary endpoints: TSS50 response (≥50% total symptom score reduction) per MFSAF v4.0 at wk 24, safety and PK. Exploratory: changes in plasma levels of proinflammatory cytokines and bone marrow (BM) morphology/fibrosis. Pts with an assessment at or post wk 24 and those who discontinued after wk 12 are included in the analysis of the corresponding endpoint.
As of 17 April 2020, 44 pts have been treated in the TD cohort (median treatment duration as of data cut: 25.6 wks, range: 1.1, 142.7 wks). Baseline characteristics: mean age 70.5 years old (yo) (SD: 8.9), 65.9% male, 95.5% with hemoglobin <10g/dL, 97.7% with DIPSS ≥Int-2, 77.3% with primary MF, 52.3% with high-molecular-risk mutations, 56.8% with JAK2, 20.5% with CALR, and 6.8% with MPL mutations. 34.4% (11/32) of TD pts converted to TI. At wk 24, 20.8% (5/24) pts achieved SVR35 (median change: -21.9%, range: -53.6%, 47.9%), and 46.2% (12/26) pts achieved TSS50 (median change: -52.8%, range: -100%, 24.4%).
In non-TD cohort, 26 pts were treated (median treatment duration as of data cut: 29.1 wks, range: 1.9, 111.3 wks). Baseline characteristics: mean age 62.9 yo (SD: 7.5), 50% male, 73.1% with DIPSS ≥Int-2, 53.8% with primary MF, 76.9% with high-molecular-risk mutations, 80.8% with JAK2, 11.5% with CALR, and 11.5% with MPL mutations. At wk 24, 22.2% (4/18) pts achieved SVR35 (median change: -15.8%, range: -89.8%, 16.3%), and 36.8% (7/19) pts achieved TSS50 (median change: -45.0%, range: -100%, 21.9%).
70 pts were evaluable for safety across the TD and non-TD cohorts. Median exposure was 28.4 wks. The most common hematological treatment-emergent adverse events (TEAEs) of any grade were thrombocytopenia (47.1%, ≥Gr3: 24.3%) and anemia (11.4%, ≥Gr3: 8.5%). The most common non-hematological TEAEs were diarrhea (51.4%, ≥Gr3: 4.3%), respiratory tract infections (35.7%, ≥Gr3: 4.3%), nausea (35.7%, ≥Gr3: 2.9%), cough (24.3%, no ≥Gr3), fatigue (22.9%, ≥Gr3: 5.7%), dysgeusia (21.4%, no ≥Gr3) and abdominal pain (20.0%, ≥Gr3: 1.4%). 7 pts 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 TD pts as assessed by conversion to TI, SVR, and symptomatic responses. SVR and symptomatic benefit were also observed in non-TD patients.
Disclosures: Verstovsek: Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding. Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Kremyanskaya: Protagonist Therapeutics: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Research Funding. Hoffman: Forbius: Consultancy; Protagonist: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding. Rampal: Pharmaessentia: Consultancy; Abbvie: Consultancy; Stemline: Consultancy, Research Funding; Galecto: Consultancy; Blueprint: Consultancy; Constellation: Research Funding; Jazz Pharmaceuticals: Consultancy; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy; Promedior: Consultancy; Celgene: Consultancy. Gupta: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Incyte: Honoraria, Research Funding. Talpaz: Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; IMAGO: Consultancy; Takeda: Research Funding; Novartis: Research Funding. Leber: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vannucchi: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bose: Pfizer, Inc.: Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Blueprint Medicines Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. McMullin: BMS: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ribrag: F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AZD: Honoraria, Other; Eisai: Honoraria; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; argenX: Current equity holder in publicly-traded company, Research Funding; Institut Gustave Roussy: Current Employment. Luptakova: Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Christo: Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Wang: Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Mertz: Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Colak: Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Shao: Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Bobba: Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Trojer: Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Senderowicz: Puma Biotechnology: Membership on an entity's Board of Directors or advisory committees; Constellation Pharmaceuticals: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months. Harrison: Shire: Honoraria, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau; Roche: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Incyte Corporation: Speakers Bureau; Sierra Oncology: Honoraria; AOP Orphan Pharmaceuticals: Honoraria; Promedior: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau.
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