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4346 BMS-986158, a Potent BET Inhibitor, As Monotherapy and in Combination with Ruxolitinib or Fedratinib in Intermediate- or High-Risk Myelofibrosis: First Results from a Phase 1/2 Study

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, MPN, Non-Biological therapies, Clinical Research, Chronic Myeloid Malignancies, Diseases, Therapies, Myeloid Malignancies, Study Population, Human
Monday, December 12, 2022, 6:00 PM-8:00 PM

Rosa Ayala1*, Nieves Lopez1*, Adi Shacham Abulafia, MD2*, Maan Alwan3*, Costas K. Yannakou, MBBS4*, Indu Raman4*, Vincent Ribrag, MD5, Chun Yew Fong, MBBS, PhD, FRACP, FRCPA6, Yulia Volchek7*, Massimiliano Bonifacio, MD8*, Alessandra Tucci, MD9*, Jean-Jacques Kiladjian, MD10, Henry Chang11*, Sharmila Das12*, Bin Wu13*, Palanikumar Ravindran14*, Vivian Shan12*, Guan Wang14*, Oriana Esposito15*, Yu Liu13*, Zariana Nikolova15*, Christopher Tehlirian13*, Shodeinde Coker14* and David Lavie, MD16*

1Hematology and Hemotherapy Department, Hospital Universitario 12 de Octubre, CNIO, Complutense University, CIBERONC, Madrid, Spain
2Institute of Hematology, Davidoff Cancer Centre, Beilinson Hospital, Rabin Medical Centre, Petah-Tiqva, Israel
3Perth Blood Institute, West Perth, Western Australia, Australia
4Epworth HealthCare, Melbourne, VIC, Australia
5Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy Institute of Cancer, Villejuif, France
6Department of Haematology, Austin Hospital, Heidelberg, VIC, Australia
7Department of Hematology, Assaf Harofeh Medical Center, Zeriffin, Israel
8Department of Medicine, Section of Hematology, University of Verona and Azienda Ospedaliera Universitaria Integrata, Verona, Italy
9Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
10Centre d'Investigations Cliniques (CIC 1427), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, INSERM, Université Paris 7, Paris, France
11Bristol Myers Squibb, San Francisco, CA
12Bristol Myers Squibb, Princeton, NJ
13Bristol Myers Squibb, Cambridge, MA
14Bristol Myers Squibb, Lawrenceville, NJ
15Centre for Innovation and Translational Research Europe, A Bristol Myers Squibb Company, Seville, Spain
16Hadassah Medical Center, Jerusalem, Israel

Background

Bromodomain and extraterminal (BET) proteins play a role in cancer-cell proliferation, survival, and oncogenic progression, providing a rationale for using inhibitors of BET as anticancer drugs. BET inhibitors (BETi) alone and in combination with Janus kinase (JAK) inhibitors have been demonstrated to reduce inflammatory signals and disease burden in mouse myelofibrosis (MF) models, and combined inhibition of BET-mediated pathways and the JAK-STAT pathway has shown additional benefits for patients (pts) with MF. BMS-986158 is an orally bioavailable, potent, and selective small-molecule BETi that has demonstrated a dose-proportional pharmacokinetic profile with linear increases in exposure, as well as time- and dose-dependent modulation of BET target gene expression (Hilton J et al. Ann Oncol 2018;29(suppl 8):1429). BMS-986158 is being evaluated in pts with MF, alone and in combination with the JAK inhibitors ruxolitinib (RUX) or fedratinib (FED), in the CA011-023 study (NCT04817007). Here, we present initial safety and efficacy data from the dose-escalation parts (1A and 1B) of this study.

Methods

CA011-023 comprises a dose-escalation phase with BMS-986158 + RUX in RUX-naive pts (Part 1A) or BMS-986158 + FED in pts with previous RUX treatment (Part 1B), and a dose-expansion phase at the Recommended Phase 2 Dose (RP2D) evaluating BMS-986158 + RUX (Part 2A) or BMS‑986158 ± FED (Part 2B). Eligible pts had primary or secondary MF, splenomegaly (spleen volume ≥ 450 cm3), ECOG performance status ≤ 2, and Dynamic International Prognostic Scoring System risk scores of intermediate-1 with symptoms, intermediate-2, or high. Planned dose levels for pts in Part 1A are BMS‑986158 2.0 mg, 3.0 mg, and 4.5 mg once daily (QD) 5 days on/2 days off and RUX 15 mg twice daily. For pts in Part 1B, planned dose levels are BMS-986158 0.5 mg, 0.75 mg, 1.25 mg, and 2.0 mg QD 5 days on/2 days off and FED 400 mg QD. Primary objectives in the dose-escalation phase are assessment of safety and tolerability and determination of the maximum tolerated dose and/or RP2D of BMS-986158 in combination with RUX or FED. Secondary objectives include spleen volume reduction (SVR) from baseline. Assessment of pharmacodynamic markers, such as JAK2 variant allele, is an exploratory objective.

Results

As of May 31, 2022, 13 pts were treated, 6 with BMS-986158 + RUX (median 66 years [range, 36–81]; 100% male) and 7 with BMS-986158 + FED (median 62 years [range, 37–77]; 57% male). Grade 1/2 treatment-related adverse events (TRAEs) were reported in 3 (50%) pts in the BMS-986158 + RUX group and in 2 (29%) pts in the BMS-986158 + FED group. Grade 3 TRAEs considered to be related to the combination treatment reported in the BMS-986158 + RUX group were thrombocytopenia (2 pts [33%]), and neutropenia and hypertension (1 pt each [17%]). Grade 3 TRAEs considered to be related to the combination treatment in the BMS-986158 + FED group were anemia (2 pts [29%]) and thrombocytopenia (1 pt [14%]). No grade 4/5 TRAEs were reported for either combination. One dose-limiting toxicity (DLT; grade 3 thrombocytopenia leading to dose reduction of BMS-986158) was reported at the 2.0 mg dose level of BMS-986158 + RUX on cycle 1 day 19. No DLTs have been reported in pts treated with BMS-986158 + FED. No serious TRAEs or TRAEs leading to treatment discontinuation have been reported. Importantly, SVR was observed at Week 12 in all evaluable pts across both treatment groups and continued to deepen at Week 24 in evaluable pts. In the BMS-986158 + RUX group, 4/5 (80%) pts met SVR35 at week 12, and 2/2 (100%) pts met SVR35 at week 24. In the BMS-986158 + FED group 0/3 (0%) pts met SVR35 at week 12, and 1/2 (50%) pts met SVR35 at week 24 (Table 1). Pts with post-baseline spleen volume by MRI in Part 1B were treated at lower BMS-986158 dose levels (0.5 mg and 0.75 mg 5 days on/2 days off) compared to Part 1A (2 mg 5 days on/2 days off). Analysis of JAK2 variant allele frequency and determination of RP2D are ongoing.

Conclusions

Most TRAEs were grade 1/2 in severity, while grade 3 TRAEs were successfully managed with dose delays or modifications without leading to treatment discontinuation. Initial results demonstrate that BMS-986158 in combination with RUX or FED produced robust SVR in pts with MF, with responses that deepened beyond Week 12 under continued treatment. Enrollment is continuing in the dose-escalation cohorts to establish RP2D for both combinations.

Disclosures: Ayala: Astellas: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Altum Sequencing: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Raman: Epworth Health: Current Employment; Snowdome Foundation: Research Funding. Ribrag: Pharmamar: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Abbvie: Speakers Bureau; Epizyme: Research Funding; GSK: Research Funding; Astex: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Fong: Pfizer: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Tucci: Takeda: Honoraria; Kiowa Kyrin: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria. Kiladjian: AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: 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. Chang: Bristol Myers Squibb: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Das: Deciphera Pharmaceuticals Inc./Beacon Hill: Ended employment in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Wu: Agios: Ended employment in the past 24 months; Patents: Patents & Royalties: IDH1 inhibitors for the treatment of haematological malignancies and solid tumours (PCT/US2016/064845); Bristol Myers Squibb: Current Employment. Ravindran: Bristol Myers Squibb: Current Employment. Shan: Syneos Health Inc.: Current Employment, Current equity holder in publicly-traded company; Bristol Myers Squibb: Consultancy. Wang: Bristol Myers Squibb: Current Employment; Merck: Ended employment in the past 24 months. Esposito: Bristol Myers Squibb: Current Employment. Liu: Bristol Myers Squibb: Current Employment. Nikolova: Bristol Myers Squibb: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Tehlirian: Bristol Myers Squibb: Current Employment; Pfizer: Ended employment in the past 24 months. Coker: Bristol Myers Squibb: Current Employment; Patents: Patents & Royalties: Fc-IL10 patent, BET inhibitor patent.

*signifies non-member of ASH