| Autor: |
Piha-Paul, Sarina A, Hann, Christine L, French, Christopher A, Cousin, Sophie, Braña, Irene, Cassier, Phillippe A, Moreno, Victor, Bono, Johann S de, Harward, Sara Duckworth, Ferron-Brady, Geraldine, Barbash, Olena, Wyce, Anastasia, Wu, Yuehui, Horner, Thierry, Annan, Meg, Parr, Nigel J, Prinjha, Rabinder K, Carpenter, Christopher L, Hilton, John, Hong, David S |
| Předmět: |
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| Zdroj: |
JNCI Cancer Spectrum; Apr2020, Vol. 4 Issue 2, p1-9, 9p |
| Abstrakt: |
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 + 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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