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2163 CPI-0610, a Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, As Monotherapy in Advanced Myelofibrosis Patients Refractory/Intolerant to JAK Inhibitor: Update from Phase 2 MANIFEST Study

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Poster II
Hematology Disease Topics & Pathways:
Diseases, MPN, Myeloid Malignancies
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Moshe Talpaz, MD1, Raajit K. Rampal, MD, PhD2, Srdan Verstovsek, MD, PhD3, Claire Harrison, DM, FRCPath4, Mark W. Drummond, PhD, FRCPath5*, Jean-Jacques Kiladjian, MD, PhD6, Alessandro Vannucchi, MD7, Marina Kremyanskaya8, Gary J. Schiller, MD9, Andrea Patriarca, MD10*, Gwendolyn Van Gorkom11*, Prithviraj Bose, MD12, Ronald Hoffman, MD13, Katarina Luptakova, MD14*, Jessica Christo, MA14*, Jing Wang, PhD14*, Jennifer A Mertz, PhD14*, Gozde Colak, PhD15*, James Shao, MS14*, Suresh Bobba, MD14*, Patrick Trojer, PhD14*, Adrian Senderowicz, MD14* and John Mascarenhas, MD8

1Rogel Cancer Center, The University of Michigan, Ann Arbor, MI
2Leukemia Service, Department of Medicine, Clinical Director, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Guy's and St Thomas' Hospital, London, United Kingdom
5Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
6Clinical Investigations Center, Saint-Louis hospital, Université de Paris, Paris, France
7Azienda Ospedaliero Universitaria Careggi, Firenze, Italy
8Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY
9David Geffen School of Medicine at UCLA, Los Angeles, CA
10Azienda Ospedaliero Universitaria Maggiore della Carità di Novara SCDU Ematologia, Novara, Italy
11University Hospital Maastricht, Maastricht, NLD
12Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX
13Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
14Constellation Pharmaceuticals, Cambridge, MA
15Constellation Pharmaceuticals, CAMBRIDGE, MA

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). Many MF patients (pts) have suboptimal responses or are resistant to the JAK inhibitor (JAKi) ruxolitinib (rux) or develop anemia and transfusion dependence (TD), which may lead to discontinuation. Here we present results from Arm 1 of MANIFEST, an ongoing, global, open-label Phase 2 study investigating CPI-0610 monotherapy in advanced MF pts refractory/intolerant to JAKi.

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 intolerant/resistant/refractory/lost response to or ineligible for JAKi, DIPSS ≥Int-2, platelets ≥75 x 109/L, ≥2 symptoms measurable (score ≥ 1) per MFSAF v4.0, RBC TD per IWG-MRT criteria in TD cohort or spleen volume of ≥ 450 cc by CT/MRI in non-TD cohort. 1° endpoints-TD cohort: TD to TI (transfusion independence) [defined as no transfusion for 12 wks per IWG-MRT]; non-TD cohort: SVR35 (≥35% spleen volume reduction) at wk 24. 2° endpoints: TSS50 (≥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 assessment at or post wk 24 and those discontinued after wk 12 are included in the analysis of the corresponding endpoint.

As of 17 Apr 2020, 27 pts were treated in non-TD cohort (median: 34.4 wks, range: 2, 123.3). Baseline characteristics: mean age 68.3 years old (yo) (SD: 9.0), 51.9% male, 81.4% with DIPSS ≥Int-2, 63.0% with hemoglobin <10g/dL, 70.4% with primary MF, 51.9% with high molecular risk, 63.0% with JAK2, 22.2% with CALR, and 7.4% with MPL mutations. Median time since MF diagnosis: 5.5 yrs (range: 0.0-19.7). Median number of prior lines of therapies: 2 (range: 1-5). Median time since last rux dose: 9.2 months (range: 0.5, 45.8). At wk 24, 23.8% (5/21) pts achieved SVR35 (median change: -28.2%, range: -51.0%, 14.4%), 47.4% (9/19) pts achieved TSS50 (median change: -55.6%, range: -100%, 24.7%). At wk 12, 17.4% (4/23) pts achieved SVR35 (median change: -19.9%, range: -62.8%, 18.0%), 30.0% (6/20) pts achieved TSS50 (median change: -26.2%, range: -100%, 23.2%). 57.9% (11/19) pts achieved ≥1.5 g/dL increase in hemoglobin (Hgb) levels without transfusion during the previous 12 wks. Improvements in BM fibrosis were also observed.

In TD cohort, 16 pts were treated (median: 28.9 wks, range: 7.9, 62.6). Baseline characteristics: mean age 71.9 yo (SD: 8.7), 68.8% male, 93.8% with DIPSS ≥Int-2, 93.8% with Hgb <10g/dL, 62.5% with primary MF, 56.3% with high-molecular-risk, 68.8% with JAK2, 18.8% with CALR, and 12.5% with MPL mutations. Median time since MF diagnosis: 4.1 yrs (range: 0.3-33.8). Median number of prior lines of therapies: 2 (range: 1-6). 43.8% of the patients received erythropoietin stimulating therapy prior to enrollment. 21.4% (3/14) of TD pts converted to TI. At wk 24, median spleen volume change is -17.4% (range: -33.8%, 64.7%); 0/10 achieved SVR35. 8.3% (1/12) pts achieved TSS50 (median change: -5.8%, range: -69.9%, 31.7%) at 24 wks. At wk 12, 28.6 % (4/14) pts achieved SVR35 (median change: -15.3%, range: -73.7%, 51.6%), 42.9% (6/14) pts achieved TSS50 (median change: -30.7%, range: -100%, 37.0%).

43 pts were evaluable for safety across cohorts. Median exposure was 34.4 wks. The most common hematological treatment-emergent adverse events (TEAEs) of any grade were thrombocytopenia (25.6%, ≥Gr3: 14%) and anemia (11.6%, ≥Gr3: 9.3%). The most common non-hematological TEAEs were nausea (32.6%, no ≥Gr3), diarrhea (30.2%, ≥Gr3: 4.7%), respiratory tract infections (27.9%, ≥Gr3: 2.3%), dysgeusia and cough (27.9% each, no ≥Gr3), and fatigue (20.9%, no ≥Gr3). 6 pts discontinued treatment because of TEAEs. There were no Gr5 TEAEs.

The results indicate that CPI-0610 monotherapy is generally well-tolerated and provides clinical benefits in MF pts refractory/intolerant to rux. SVR35 and symptomatic improvement were observed. Majority of non-TD pts demonstrated ≥1.5 g/dL increase in Hgb, a potential disease-modifying effect of CPI-0610. Conversion to TI was observed in the TD cohort.

Disclosures: Talpaz: IMAGO: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Takeda: Research Funding. Rampal: Galecto: Consultancy; Stemline: Consultancy, Research Funding; Blueprint: Consultancy; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy; Celgene: Consultancy; Promedior: Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Pharmaessentia: Consultancy; Constellation: Research Funding. Verstovsek: Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; ItalPharma: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding. Harrison: Promedior: Honoraria; AOP Orphan Pharmaceuticals: Honoraria; Roche: Honoraria; Sierra Oncology: Honoraria; Shire: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Incyte Corporation: Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Drummond: Takeda: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine Corporation: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vannucchi: 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; Blueprint: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremyanskaya: Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Schiller: Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Stemline: Speakers Bureau; Abbvie: Research Funding; Actinium: Research Funding; Forma: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; DeltaFly: Research Funding; Deciphera: Research Funding; Daiichi Sankyo: Research Funding; Cyclacel: Research Funding; Constellation: Research Funding; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau; FujiFilm: Research Funding; Gamida: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding; Jazz Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding. Bose: Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Hoffman: Novartis: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Forbius: Consultancy; Protagonist: Consultancy. 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: 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. 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).

*signifies non-member of ASH