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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.
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Details
1 University of Texas MD Anderson Cancer Center, Houston, TX
2 Johns Hopkins University School of Medicine, Baltimore, MD
3 Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
4 Medical Oncology, Institute Bergonié, Bordeaux, France
5 Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain
6 Medical Oncology, Léon Bérard Cancer Center, Lyon, France
7 Medical Oncology, START Madrid-FJD, Fundación Jiménez Díaz Hospital, Madrid, Spain
8 The Institute of Cancer Research and Royal Marsden Hospital, London, UK
9 GSK, Research Triangle Park, NC
10 GSK, Collegeville, PA
11 UCB Celltech, Slough, UK
12 Division of Medical Oncology, Ottawa Hospital Cancer Centre, Ottawa, ON, Canada
13 Rubius Therapeutics, Cambridge, MA
14 Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA
15 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA