Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors.
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Embargo End Date
ICR Authors
Authors
Piha-Paul, SA
Hann, CL
French, CA
Cousin, S
Braña, I
Cassier, PA
Moreno, V
de Bono, JS
Harward, SD
Ferron-Brady, G
Barbash, O
Wyce, A
Wu, Y
Horner, T
Annan, M
Parr, NJ
Prinjha, RK
Carpenter, CL
Hilton, J
Hong, DS
Haas, NB
Markowski, MC
Dhar, A
O'Dwyer, PJ
Shapiro, GI
Hann, CL
French, CA
Cousin, S
Braña, I
Cassier, PA
Moreno, V
de Bono, JS
Harward, SD
Ferron-Brady, G
Barbash, O
Wyce, A
Wu, Y
Horner, T
Annan, M
Parr, NJ
Prinjha, RK
Carpenter, CL
Hilton, J
Hong, DS
Haas, NB
Markowski, MC
Dhar, A
O'Dwyer, PJ
Shapiro, GI
Document Type
Journal Article
Date
2020-04-01
Date Accepted
2019-10-31
Abstract
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.
Citation
JNCI Cancer Spectrum, 2020, 4 (2), pp. pkz093 -
Source Title
JNCI Cancer Spectrum
Publisher
OXFORD UNIV PRESS
ISSN
2515-5091
eISSN
2515-5091
Collections
Research Team
PrCa Targeted Therapy