Sistema de Salut de Catalunya
Institut Català de la Salut
[Vieito M] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Simonelli M] Department of Biomedical Sciences, Humanitas University, Milan, Italy. IRCCS Humanitas Research Hospital, Milan, Italy. [de Vos F] Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. [Moreno V] START Madrid-FJD, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain. [Geurts M] Erasmus MC Cancer Institute, Rotterdam, the Netherlands. [Lorenzi E] IRCCS Humanitas Research Hospital, Milan, Italy
Vall d'Hebron Barcelona Hospital Campus
2022-12-02T09:03:36Z
2022-12-02T09:03:36Z
2022-01
BET inhibitors; Glioblastoma; Pharmacokinetics
Inhibidores de BET; Glioblastoma; Farmacocinética
Inhibidors de BET; Glioblastoma; Farmacocinètica
Background Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery followed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; however, prognosis remains poor. Trotabresib, a novel bromodomain and extraterminal inhibitor, has demonstrated antitumor activity in patients with high-grade gliomas. Methods In this phase Ib, dose-escalation study (NCT04324840), we investigated trotabresib 15, 30, and 45 mg combined with TMZ in the adjuvant setting and trotabresib 15 and 30 mg combined with TMZ+RT in the concomitant setting in patients with ndGBM. Primary endpoints were to determine safety, tolerability, maximum tolerated dose, and/or recommended phase II dose (RP2D) of trotabresib. Secondary endpoints were assessment of preliminary efficacy and pharmacokinetics. Pharmacodynamics were investigated as an exploratory endpoint. Results The adjuvant and concomitant cohorts enrolled 18 and 14 patients, respectively. Trotabresib in combination with TMZ or TMZ+RT was well tolerated; most treatment-related adverse events were mild or moderate. Trotabresib pharmacokinetics and pharmacodynamics in both settings were consistent with previous data for trotabresib monotherapy. The RP2D of trotabresib was selected as 30 mg 4 days on/24 days off in both settings. At last follow-up, 5 (28%) and 6 (43%) patients remain on treatment in the adjuvant and concomitant settings, respectively, with 1 patient in the adjuvant cohort achieving complete response. Conclusions Trotabresib combined with TMZ in the adjuvant setting and with TMZ+RT in the concomitant setting was safe and well tolerated in patients with ndGBM, with encouraging treatment durations. Trotabresib 30 mg was established as the RP2D in both settings.
This study was sponsored by Celgene, a Bristol Myers Squibb company.
Article
Published version
English
Glioblastoma multiforme - Tractament; Glioblastoma multiforme - Radioteràpia; Quimioteràpia combinada; DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Glioma::Astrocytoma::Glioblastoma; Other subheadings::Other subheadings::/therapy; ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols; ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Radiotherapy; ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::glioma::astrocitoma::glioblastoma; Otros calificadores::Otros calificadores::/terapia; TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada; TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::radioterapia
Oxford University Press
Neuro-Oncology Advances;4(1)
https://doi.org/10.1093/noajnl/vdac146
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
