CPI-0610, A BROMODOMAIN AND EXTRATERMINAL DOMAIN PROTEIN (BET) INHIBITOR, IN COMBINATION WITH RUXOLITINIB, IN JAK INHIBITOR TREATMENT NAÏVE MYELOFIBROSIS PATIENTS: UPDATE FROM MANIFEST PHASE 2 STUDY
Author(s): ,
John Mascarenhas
Affiliations:
Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York,United States
,
Claire Harrison
Affiliations:
Guy's and St. Thomas' Hospital,London,United Kingdom
,
Andrea Patriarca
Affiliations:
Azienda Ospedaliero Universitaria Maggiore della Carità di Novara SCDU Ematologia,Novara,Italy
,
Timothy Devos
Affiliations:
Department of Hematology, University Hospitals Leuven and Laboratory of Molecular Immunology, Rega Institute,Leuven,Belgium
,
Francesca Palandri
Affiliations:
Institute of Hematology 'L. & A. Seragnoli', University of Bologna,Bologna,Italy
,
Raajit Rampal
Affiliations:
Memorial Sloan-Kettering Cancer Center,New York,United States
,
Adam Mead
Affiliations:
Oxford University Hospitals,Oxford,United Kingdom
,
Marina Kremyanskaya
Affiliations:
Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York,United States
,
Tim Somervaille
Affiliations:
Cancer Research UK Manchester Institute & The Christie Hospital,Manchester,United Kingdom
,
Marielle Wondergem
Affiliations:
Department of Hematology, Academisch Ziekenhuis Vrije Universiteit,Amsterdam,Netherlands
,
Ronald Hoffman
Affiliations:
Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York,United States
,
Sujan Kabir
Affiliations:
Constellation Pharmaceuticals,Boston,United States
,
Jennifer Mertz
Affiliations:
Constellation Pharmaceuticals,Boston,United States
,
Gozde Colak
Affiliations:
Constellation Pharmaceuticals,Boston,United States
,
James Shao
Affiliations:
Constellation Pharmaceuticals,Boston,United States
,
Suresh Bobba
Affiliations:
Constellation Pharmaceuticals,Boston,United States
,
Patrick Trojer
Affiliations:
Constellation Pharmaceuticals,Boston,United States
,
Adrian Senderowicz
Affiliations:
Constellation Pharmaceuticals,Boston,United States
,
Srdan Verstovsek
Affiliations:
Department of Leukemia, University of Texas MD Anderson Cancer Center,Houston,United States
Vikas Gupta
Affiliations:
Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada
EHA Library. Mascarenhas D. 06/12/20; 293573; EP1084
Dr. Dr. John Mascarenhas
Dr. Dr. John Mascarenhas
Contributions
Abstract

Abstract: EP1084

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
BET proteins are transcriptional regulators of oncogenic pathways and important drivers of inflammation in myelofibrosis (MF). CPI-0610, an oral, selective small molecule BET bromodomain inhibitor (BETi), 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. Historically, rux achieved ≥35% spleen volume reduction (SVR35) and ≥50% total symptom score improvement (TSS50) in 29-42% and 42-46% of pts, respectively, at wk 24 (COMFORT-I, SIMPLIFY-1). However, ≥Gr3 anemia (45.2%) and thrombocytopenia (12.9%) are concerns of rux treatment. Disease-modifying therapeutic agents are needed to improve the outcomes in MF pts. We report the updated safety and efficacy data from Arm 3 of the MANIFEST study.

Aims
To evaluate CPI-0610 + Rux in JAKi treatment naïve MF pts.

Methods
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. Endpoints: 1°- SVR35 at wk 24; key 2°- TSS50 at wk 24; others: safety, PK, changes in proinflammatory cytokines and bone marrow (BM) morphology/fibrosis.

Results
As of 9 Jan 2020, 53 pts treated. Baseline median age: 69 (range: 37-85); 39 (73.6%) male; primary MF: 25 (47.2%) pts; DIPSS ≥Int-2: 39 (73.6%) pts; 32 (60.4%) pts anemic (Hgb <10g/dL); median platelet: 345 x 109/L (range: 100-1849); median spleen volume: 1726.5 cc (range: 457-7842); median TSS: 14 (range: 0-38); mutational status JAK2: 39 (73.6%); CALR: 11 (20.8%); MPL: 2 (3.8%); high molecular risk: 27 (50.9%) pts. 15 pts were evaluable for SVR35 at wk 24, including 14 pts received ≥24 wks of treatment and 1 pt discontinued prior to wk 24; 66.7% (10/15) pts achieved SVR35 at wk 24 (median change -54%; range: -83.8%, -30.6%), and all 14 pts assessed at wk 24 achieved an SVR of at least 30%. 14 pts were evaluable for TSS50 at wk 24 (1 pt missing baseline evaluation); 78.6% (11/14) pts achieved TSS50 at wk 24 (median change -71.9%; range: -100%, 4.9%). 45.5% (5/11) pts had improvement in BM fibrosis by ≥ 1 grade after 6 months of treatment. 1 pt discontinued study to undergo bone marrow transplantation after 24 wks of treatment.

53 pts were safety evaluable. The most common hematological treatment-emergent adverse events (TEAEs) of any grade were anemia (20.8%, ≥Gr3: 15.1%) and thrombocytopenia (17%, ≥Gr3: 5.7%). These cytopenias were generally manageable with dose modifications, including reductions/interruptions. The most common non-hematological TEAEs were diarrhea (24.5%, No ≥Gr3), nausea (20.8%, No ≥Gr3), infections (15.1%, ≥Gr3: 3.8%), dysgeusia (11.3%, No ≥Gr3), and dyspnea (11.3%, ≥Gr3: 3.8%). 2 pts discontinued treatment due to AEs (infections unrelated to CPI-0610); 1 of them died within 30 days of treatment discontinuation.

Conclusion
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. In addition, improvements in BM fibrosis and low incidence of ≥Gr3 anemia (a known AE for JAKi), were observed. Overall, the data suggest that the addition of CPI-0610 to rux is potentially synergistic and disease modifying in JAKi naïve MF pts. We anticipate starting a Phase 3 study in 2H 2020.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Epigenetic, Myelofibrosis, Ruxolitinib

Abstract: EP1084

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
BET proteins are transcriptional regulators of oncogenic pathways and important drivers of inflammation in myelofibrosis (MF). CPI-0610, an oral, selective small molecule BET bromodomain inhibitor (BETi), 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. Historically, rux achieved ≥35% spleen volume reduction (SVR35) and ≥50% total symptom score improvement (TSS50) in 29-42% and 42-46% of pts, respectively, at wk 24 (COMFORT-I, SIMPLIFY-1). However, ≥Gr3 anemia (45.2%) and thrombocytopenia (12.9%) are concerns of rux treatment. Disease-modifying therapeutic agents are needed to improve the outcomes in MF pts. We report the updated safety and efficacy data from Arm 3 of the MANIFEST study.

Aims
To evaluate CPI-0610 + Rux in JAKi treatment naïve MF pts.

Methods
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. Endpoints: 1°- SVR35 at wk 24; key 2°- TSS50 at wk 24; others: safety, PK, changes in proinflammatory cytokines and bone marrow (BM) morphology/fibrosis.

Results
As of 9 Jan 2020, 53 pts treated. Baseline median age: 69 (range: 37-85); 39 (73.6%) male; primary MF: 25 (47.2%) pts; DIPSS ≥Int-2: 39 (73.6%) pts; 32 (60.4%) pts anemic (Hgb <10g/dL); median platelet: 345 x 109/L (range: 100-1849); median spleen volume: 1726.5 cc (range: 457-7842); median TSS: 14 (range: 0-38); mutational status JAK2: 39 (73.6%); CALR: 11 (20.8%); MPL: 2 (3.8%); high molecular risk: 27 (50.9%) pts. 15 pts were evaluable for SVR35 at wk 24, including 14 pts received ≥24 wks of treatment and 1 pt discontinued prior to wk 24; 66.7% (10/15) pts achieved SVR35 at wk 24 (median change -54%; range: -83.8%, -30.6%), and all 14 pts assessed at wk 24 achieved an SVR of at least 30%. 14 pts were evaluable for TSS50 at wk 24 (1 pt missing baseline evaluation); 78.6% (11/14) pts achieved TSS50 at wk 24 (median change -71.9%; range: -100%, 4.9%). 45.5% (5/11) pts had improvement in BM fibrosis by ≥ 1 grade after 6 months of treatment. 1 pt discontinued study to undergo bone marrow transplantation after 24 wks of treatment.

53 pts were safety evaluable. The most common hematological treatment-emergent adverse events (TEAEs) of any grade were anemia (20.8%, ≥Gr3: 15.1%) and thrombocytopenia (17%, ≥Gr3: 5.7%). These cytopenias were generally manageable with dose modifications, including reductions/interruptions. The most common non-hematological TEAEs were diarrhea (24.5%, No ≥Gr3), nausea (20.8%, No ≥Gr3), infections (15.1%, ≥Gr3: 3.8%), dysgeusia (11.3%, No ≥Gr3), and dyspnea (11.3%, ≥Gr3: 3.8%). 2 pts discontinued treatment due to AEs (infections unrelated to CPI-0610); 1 of them died within 30 days of treatment discontinuation.

Conclusion
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. In addition, improvements in BM fibrosis and low incidence of ≥Gr3 anemia (a known AE for JAKi), were observed. Overall, the data suggest that the addition of CPI-0610 to rux is potentially synergistic and disease modifying in JAKi naïve MF pts. We anticipate starting a Phase 3 study in 2H 2020.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Epigenetic, Myelofibrosis, Ruxolitinib

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