TY - JOUR
T1 - Phase 1 study of molibresib (GSK525762), a bromodomain and extra-terminal domain protein inhibitor, in NUT carcinoma and other solid tumors
AU - Piha-Paul, Sarina A.
AU - Hann, Christine L.
AU - French, Christopher A.
AU - Cousin, Sophie
AU - Braña, Irene
AU - Cassier, Phillippe A.
AU - Moreno, Victor
AU - de Bono, Johann S.
AU - Harward, Sara Duckworth
AU - Ferron-Brady, Geraldine
AU - Barbash, Olena
AU - Wyce, Anastasia
AU - Wu, Yuehui
AU - Horner, Thierry
AU - Annan, Meg
AU - Parr, Nigel J.
AU - Prinjha, Rabinder K.
AU - Carpenter, Christopher L.
AU - Hilton, John
AU - Hong, David S.
AU - Haas, Naomi B.
AU - Markowski, Mark C.
AU - Dhar, Arindam
AU - O’Dwyer, Peter J.
AU - Shapiro, Geoffrey I.
N1 - Funding Information:
This study (BET115521; NCT01587703) was supported by GlaxoSmithKline (GSK). Financial support for this work was also provided by National Institutes of Health (NIH) Cancer Center Support Grants P30 CA016672 and P30 CA006516, as well as NIH grant R01 CA124633 to CAF.
Publisher Copyright:
© The Author(s) 2019.
PY - 2020
Y1 - 2020
N2 - Background: Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors. Methods: This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 þ 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker. Results: Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60–100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%–42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3–7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months. Conclusions: Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC.
AB - Background: Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors. Methods: This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 þ 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker. Results: Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60–100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%–42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3–7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months. Conclusions: Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC.
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U2 - 10.1093/JNCICS/PKZ093
DO - 10.1093/JNCICS/PKZ093
M3 - Article
AN - SCOPUS:85088641272
SN - 2515-5091
VL - 4
JO - JNCI Cancer Spectrum
JF - JNCI Cancer Spectrum
IS - 2
M1 - PKZ093
ER -