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Clinical Trial
. 2022 Aug 11;2(8):795-805.
doi: 10.1158/2767-9764.CRC-22-0060. eCollection 2022 Aug.

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

Kristie A Blum  1 , Jeffrey G Supko  2 , Michael B Maris  3 , Ian W Flinn  4 , Andre Goy  5 , Anas Younes  6 , Suresh Bobba  7 , Adrian M Senderowicz  7 , Sergey Efuni  7 , Ronda Rippley  7 , Gozde Colak  7 , Patrick Trojer  7 , Jeremy S Abramson  2
Affiliations
Clinical Trial

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

Kristie A Blum et al. Cancer Res Commun. .

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.

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Conflict of interest statement

K.A. Blum reports grants from Constellation Pharmaceuticals during the conduct of the study. J.G. Supko reports other from Constellation Pharmaceuticals during the conduct of the study. M.B. Maris reports other from Constellation Pharmaceuticals during the conduct of the study. I.W. Flinn reports grants from Constellation Pharmaceuticals during the conduct of the study; other from Abbvie, other from Astrazeneca, other from Beigene, other from Century Therapeutics, other from Genentech, other from Gilead Sciences, other from Great Point Partners, other from Hutchison Medipharma, other from Iksuda Therapeutics, other from Innocare Pharma, other from Janssen, other from Juno Therapeutics, other from Kite Pharma, other from Morphosys, other from Nurix Therapeutics, other from Pharmacyclics, other from Roche, other from Seattle Genetics, other from Servier Pharmaceuticals, other from Takeda, other from TG Therapeutics, other from Unum Therapeutics, other from Verastem, other from Vincerx Pharma, other from Yingli Pharmaceuticals, grants from Abbvie, grants from Acerta Pharma, grants from Agios, grants from Arqule, grants from Astrazeneca, grants from Beigene, grants from Biopath, grants from Bristol Myers Squibb, grants from Calibr, grants from Calgb, grants from Celgene, grants from City of Hope National Medical Center, grants from Constellation Pharmaceuticals, grants from Curis, grants from CTI Biopharma, grants from Fate Therapeutics, grants from Forma Therapeutics, grants from Forty Seven, grants from Genentech, grants from Gilead Sciences, grants from Innocare Pharma, grants from IGM Biosciences, grants from Incyte, grants from Infinity Pharmaceuticals, grants from Janssen, grants from Kite Pharma, grants from Loxo, grants from Merck, grants from Millennium Pharmaceuticals, grants from Morphosys, grants from Myeloid Therapeutics, grants from Novartis, grants from Nurix, grants from Pfizer, grants from Pharmacyclics, grants from Portola Pharmaceuticals, grants from Rhizen Pharmaceuticals, grants from Roche, grants from Seattle Genetics, grants from Tessa Therapeutics, grants from TCR2, grants from TG Therapeutics, grants from Trillium Therapeutics, grants from Triphase Research & Development Corp, grants from Unum Therapeutics, and grants from Verastem outside the submitted work. A. Goy reports other from Acerta, personal fees and other from AstraZeneca, personal fees and other from Bristol Myers, personal fees and other from Celgene, other from Genentech, personal fees and other from Hoffman La Roche, other from Infinity, personal fees and other from Janssen, other from Karyopharm, personal fees and other from Kite Pharma, personal fees and other from MorphoSys, other from Pharmacyclics, other from Seattle Genetics, other from Verastem, personal fees and other from Alloplex, personal fees and other from Clinical Advances in Hematology & Oncology, personal fees and other from COTA, personal fees and other from Elsevier's PracticeUpdate Oncology, personal fees and other from GENOMIC TESTING COOPERATIVE, LCA, personal fees and other from Gilead, personal fees and other from Medscape, personal fees and other from Michael J Hennessey Associates, INC, personal fees and other from Novartis, personal fees and other from Onclive Peer Exchange, personal fees and other from Physcians Education Resource, LLC, personal fees and other from Rosewell Park, personal fees and other from Resilience, personal fees and other from Vincerx, and personal fees and other from Xcenda-Amerisource outside the submitted work. A. Younes reports other from AstraZeneca during the conduct of the study; other from AstraZeneca outside the submitted work. A.M. Senderowicz reports a patent to USE PELABRESIB IN MYELOFIBROSIS pending. G. Colak reports being an employee of Constellation Pharmaceuticals. J.S. Abramson reports grants from Constellation during the conduct of the study. No other disclosures were reported.

Figures

FIGURE 1
FIGURE 1
Relationship between pelabresib and platelet count values. A, Day 14 platelet count as a function of steady state AUC of pelabresib. B, Day 14 mean platelet count as a percent of baseline compared with pelabresib mean AUC. The coefficient of determination (R2) = 0.8122, obtained from a simple linear regression model with mean platelet count ratio as the dependent variable and pelabresib capsule dose as the independent variable (tablet doses were multiplied by 1.34 to convert to capsule doses). C, Mean platelet count over time. AUC, area under the curve; CPI-0610, pelabresib; CXDX, Cycle number Day number; X mg C, Capsule pelabresib dose; X mg T, Tablet pelabresib dose.
FIGURE 2
FIGURE 2
Mean pelabresib plasma profiles and dose proportionality. A, Mean pelabresib plasma profile over time at Cycle 1 Day 1. B, Mean pelabresib plasma profile over time at Cycle 1 Day 14. C, Dose proportionality of mean steady-state AUC of patients treated with capsule and tablet doses of pelabresib. Subjects receiving a dose other than the planned dose were excluded from the calculation of concentration summary statistics; Predose/negative nominal time were set to 0.
FIGURE 3
FIGURE 3
Gene expression analysis of IL8 and CCR1 transcript levels after treatment with pelabresib. A, Relative expression of IL8 blood mRNA levels prior to and 2, 6, and 8 hours after pelabresib treatment. B, Relative expression of CCR1 blood mRNA levels prior to and 2, 6, and 8 hours after pelabresib treatment. Relative mRNA expression of IL8 and CCR1 after dosing is shown relative to the pretreatment values (y axis). C, Relative IL8 and CCR1 mRNA expression compared to the Cycle 1 Day 14 steady-state AUC. IL8 and CCR1 are represented as the average at the 2-hour time point following pelabresib administration over that of baseline in each dose group. The steady state (C1D14) AUC0–24 (hour/ng/mL, geometric mean of each dose level) is shown on the right y axis. T = tablet 125 mg and 225 mg were tablet formulations; all other doses were capsule formulation.
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