A Phase I Study of Pelabresib (CPI-0610), a Small-Molecule Inhibitor of BET Proteins, in Patients with Relapsed or Refractory Lymphoma.

• Type of Material: Article
• Authors: Kristie Blum, Emory University; Jeffrey G Supko, Massachusetts General Hospital, Boston, Massachusetts.; Michael B Maris, Colorado Blood Cancer Institute, Denver, Colorado.; Ian W Flinn, Sarah Cannon Research Institute and Tennessee Oncology PLLC, Nashville, Tennessee.; Andre Goy, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.; Anas Younes, Memorial Sloan Kettering Cancer Center, New York City, New York.; Suresh Bobba, Constellation Pharmaceuticals (a Morphosys Company), Boston, Massachusetts.; Adrian M Senderowicz, Constellation Pharmaceuticals (a Morphosys Company), Boston, Massachusetts.; Sergey Efuni, Constellation Pharmaceuticals (a Morphosys Company), Boston, Massachusetts.; Ronda Rippley, Constellation Pharmaceuticals (a Morphosys Company), Boston, Massachusetts.; Gozde Colak, Constellation Pharmaceuticals (a Morphosys Company), Boston, Massachusetts.; Patrick Trojer, Constellation Pharmaceuticals (a Morphosys Company), Boston, Massachusetts.; Jeremy S Abramson, Massachusetts General Hospital, Boston, Massachusetts.
• Language: English
• Date: 2022-08
• Publisher: American Association for Cancer Research.
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors; Published by the American Association for Cancer Research
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1158/2767-9764.CRC-22-0060
• Title of Journal or Parent Work: Cancer Res Commun
• Volume: 2
• Issue: 8
• Start Page: 795
• End Page: 805
• Keywords: BET Proteins
• Research Categories: Health Sciences, Oncology

Abstract

PURPOSE: NF-κB, a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed/refractory lymphomas (NCT01949883). EXPERIMENTAL DESIGN: Sixty-four patients with relapsed/refractory lymphoma (median of 4 prior lines of therapy) were treated with either capsule (6, 12, 24, 48, 80, 120, 170, 230, 300 mg) or tablet (125, 225 mg) doses of pelabresib orally once daily on a 14 days on, 7 days off schedule. RESULTS: The MTD was determined as the 225 mg tablet daily. The most frequent adverse events were fatigue, nausea, and decreased appetite. Thrombocytopenia, a class effect for all BET inhibitors, was dose-dependent, reversible, and noncumulative. Pelabresib exhibited dose-proportional increases in systemic exposure, rapid absorption, and a half-life of approximately 15 hours (supporting once daily dosing). The bioavailability of the tablet formulation was 60% greater than the capsules. Pelabresib suppressed IL8 and CCR1 mRNA at doses above 120 and 170 mg, respectively. Four patients (6.2%) had an objective response (2 complete response and 2 partial response) and 5 patients had prolonged stable disease. CONCLUSIONS/DISCUSSION: Pelabresib is capable of BET target gene suppression in an exposure-dependent manner with an acceptable safety profile leading to the recommended phase II dose of the 125 mg tablet once daily. SIGNIFICANCE: BET proteins inhibition can potentially modify the pathogenic pathways which contribute to many diseases including malignancies. Pelabresib (CPI-0610), a potent and selective small molecule BET proteins inhibitor, has a MTD of 225 mg once daily for 14 days with a 7-day break, clear pharmacokinetic/pharmacodynamic relationship, and manageable clinical safety profile. These findings are part of the foundation for the ongoing pivotal study of pelabresib in patients with myelofibrosis.