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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

Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical: New Therapies and JAKi-based Combinations for Myelofibrosis
Hematology Disease Topics & Pathways:
Diseases, Bone Marrow Failure, MPN, Myeloid Malignancies
Saturday, December 5, 2020: 8:30 AM

John Mascarenhas, MD1, Claire Harrison, DM, FRCPath2, Andrea Patriarca, MD3*, Timothy Devos, MD4, Francesca Palandri, MD, PhD5*, Raajit K. Rampal, MD, PhD6, Adam J. Mead, MD, PhD7, Marina Kremyanskaya1, Tim C.P Somervaille, PhD, FRCP, FRCPath8, Marielle Wondergem, MD9*, Ronald Hoffman, MD10, Katarina Luptakova, MD11*, Jing Wang, PhD11*, Jessica Christo, MA11*, Jennifer A Mertz, PhD11*, Gozde Colak, PhD12*, James Shao, MS11*, Suresh Bobba, MD11*, Patrick Trojer, PhD11*, Adrian Senderowicz, MD11*, Srdan Verstovsek, MD, PhD13 and Vikas Gupta, MD, FRCP, FRCPath14

1Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY
2Guy's and St Thomas' Hospital, London, United Kingdom
3Azienda Ospedaliero Universitaria Maggiore della Carità di Novara SCDU Ematologia, Novara, Italy
4Department of Hematology and Department of Microbiology and Immunology, University Hospitals Leuven and Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium
5Institute of Hematology “L. and A. Seràgnoli”, S. Orsola-Malpighi Bologna University Hospital, Bologna, Italy
6Leukemia Service, Department of Medicine, Clinical Director, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
7Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
8The Christie Hospital, Cancer Research UK Manchester Institute, Manchester, United Kingdom
9Department of Hematology, Academisch Ziekenhuis Vrije Universiteit, Amsterdam, Netherlands
10Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
11Constellation Pharmaceuticals, Cambridge, MA
12Constellation Pharmaceuticals, CAMBRIDGE, MA
13Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
14Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada

The bromodomain and extraterminal domain (BET) family of proteins bind to chromatin to regulate the transcription of target genes involved in multiple pro-fibrotic pathways and is a novel therapeutic target for reducing fibrosis in myelofibrosis (MF). CPI-0610 is a unique, first-in-class, oral, small-molecule inhibitor of BET (BETi) 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 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. A minority of 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. Disease-modifying therapeutic agents are needed to improve the outcomes 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 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. Primary endpoint: SVR35 response (≥35% reduction in spleen volume) at wk 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 17 Apr 2020, 64 pts treated, 57 pts ongoing. Baseline characteristics: mean age: 67.1 years old (yo) (SD: 10.27); 70.3% male; primary MF: 51.6% pts; DIPSS ≥Int-2: 75.0% pts; 64.1% pts anemic (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% pts, JAK2 mutation: 71.9%, CALR mutation: 21.9%, and MPL mutation: 4.7%. Median rux dose: 10 mg BID; median CPI-0610 dose: 125 mg QD. 30 pts were evaluable for SVR35 at wk 24, including 28 pts received ≥24 wks of treatment and 2 pts discontinued prior to wk 24. 63.3% (19/30) pts achieved SVR35 at wk 24 (median change -52.9%; range: -84.4%, 23.7%). 29 pts were evaluable for TSS50 at wk 24 (1 pt missing baseline evaluation); 58.6% (17/29) pts achieved TSS50 at wk 24 (median change -64%; range: -100%, 24.2%). The difference in baseline disease characteristics had no bearing on the efficacy outcome as there was no correlation observed between spleen volume response at 24 wk with baseline spleen volume or baseline platelet count.

64 pts were evaluable for safety. Median exposure was 24.1 wks. The most common hematological treatment-emergent adverse events (TEAEs) of any grade were anemia (23.4%, ≥Gr3: 17.2%) and thrombocytopenia (20.3%, ≥Gr3: 4.7%). These cytopenias were generally manageable with dose modifications, including reductions/interruptions. The most common non-hematological TEAEs were diarrhea (26.6%, no ≥Gr3), respiratory tract infections (18.8%, ≥Gr3: 4.7%), nausea (18.8%, no ≥Gr3), abdominal pain (15.6%, no ≥Gr3), dysgeusia (14.1%, no ≥Gr3), fatigue (12.5%, no ≥Gr3), headache and back pain (10.9% each, no ≥Gr3). 2 pts discontinued treatment due to TEAEs (infections unrelated to CPI-0610); 1 of them died within 30 days of treatment discontinuation. 1 pt discontinued study in order to undergo allogeneic stem cell transplantation after 24 wks of treatment.

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. Overall, the data suggest that the addition of CPI-0610 to rux is potentially synergistic in JAKi-naïve MF pts.

Disclosures: 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). Harrison: Roche: Honoraria; Promedior: Honoraria; Sierra Oncology: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; CTI Biopharma Corp: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau. Devos: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palandri: Novartis: Consultancy, Honoraria. Rampal: Pharmaessentia: Consultancy; Promedior: Consultancy; Incyte: Consultancy, Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Galecto: Consultancy; Constellation: Research Funding; Stemline: Consultancy, Research Funding; Blueprint: Consultancy; Jazz Pharmaceuticals: Consultancy; CTI Biopharma: Consultancy. Mead: CTI: Consultancy; Gilead: Consultancy; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding; Abbvie: Consultancy. Kremyanskaya: Astex Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Incyte Corporation: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding. Somervaille: Novartis: Consultancy, Honoraria; Imago Bioscience: Research Funding. Hoffman: Dompe: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Forbius: Consultancy; Protagonist: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees. Luptakova: Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Wang: Constellation Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Christo: 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: Constellation Pharmaceuticals: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Puma Biotechnology: Membership on an entity's Board of Directors or advisory committees. Verstovsek: AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Promedior: Research Funding; Celgene: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Roche: Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding. Gupta: Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Bristol MyersSquibb: 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, Research Funding; Incyte: Honoraria, Research Funding.

*signifies non-member of ASH