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

by Selleckchem | Jul 02 2023

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.

Comments:

The purpose of the study was to investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pelabresib (also known as CPI-0610), an investigational BET bromodomain inhibitor, in patients with relapsed/refractory lymphomas. NF-κB, a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas, and preclinical studies had shown that pelabresib downregulated NF-κB signaling and demonstrated antitumor activity in vitro.

The study included 64 patients with relapsed/refractory lymphoma who had received a median of 4 prior lines of therapy. Pelabresib was administered orally once daily on a 14 days on, 7 days off schedule, using either capsule or tablet formulations at various doses ranging from 6 mg to 300 mg for the capsules and 125 mg to 225 mg for the tablets.

The maximum tolerated dose (MTD) was determined to be the 225 mg tablet once daily. The most common adverse events reported were fatigue, nausea, and decreased appetite. Thrombocytopenia, which is a known class effect for all BET inhibitors, was dose-dependent but reversible and noncumulative.

Pelabresib showed dose-proportional increases in systemic exposure, rapid absorption, and a half-life of approximately 15 hours, which supported once daily dosing. The bioavailability of the tablet formulation was found to be 60% greater than the capsules. Pelabresib suppressed the expression of IL8 and CCR1 mRNA at doses above 120 mg and 170 mg, respectively.

In terms of clinical activity, four patients (6.2%) achieved an objective response, including two complete responses and two partial responses. Additionally, five patients had prolonged stable disease.

The study concluded that pelabresib, as a BET proteins inhibitor, effectively suppressed target gene expression in an exposure-dependent manner and had an acceptable safety profile. The recommended phase II dose was determined to be the 125 mg tablet once daily. These findings supported the ongoing pivotal study of pelabresib in patients with myelofibrosis.

The significance of the study lies in the potential of BET protein inhibition to modify pathogenic pathways involved in various diseases, including malignancies. Pelabresib, as a potent and selective small molecule BET proteins inhibitor, demonstrated a clear pharmacokinetic/pharmacodynamic relationship, manageable clinical safety profile, and promising preliminary clinical activity. These findings laid the groundwork for further investigation of pelabresib in the treatment of myelofibrosis.