342f4593655845694bc8ead0e59827c2 pmc_9653173.pdf 7892526b8e1ba3a98c4903cd352191a669e10704 pmc_9653173.pdf 5f4629d2314f4f28b6b4262866940889abb796d665e67fe9a9293c838762c267 pmc_9653173.pdf Title: Trotabresib (CC-90010) in combination with adjuvant temozolomide or concomitant temozolomide plus radiotherapy in patients with newly diagnosed glioblastoma Subject: doi: 10.1093/noajnl/vdac146 Neuro-Oncology Advances, 10 November 2022 Abstract: 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. Author: Maria Vieito, Matteo Simonelli, Filip de Vos, Victor Moreno, Marjolein Geurts, Elena Lorenzi, Marina Macchini, Martin J van den Bent, Gianluca Del Conte, Maja de Jonge, Maria Cruz Martín-Soberón, Barbara Amoroso, Tania Sanchez-Perez, Marlene Zuraek, Bishoy Hanna, Ida Aronchik, Ellen Filvaroff, Henry Chang, Cristina Mendez, Marina Arias Parro, Xin Wei, Zariana Nikolova, Juan Manuel Sepulveda Creator: Adobe InDesign 15.1 (Windows) Producer: Adobe PDF Library 15.0 CreationDate: Thu Nov 10 06:39:37 2022 CET ModDate: Thu Nov 10 06:40:24 2022 CET Tagged: yes UserProperties: no Suspects: no Form: none JavaScript: no Pages: 11 Encrypted: no Page size: 594 x 783 pts Page rot: 0 File size: 647994 bytes Optimized: yes PDF version: 1.6 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- NUFDDT+GlyphaLTStd-Bold Type 1C Custom yes yes yes 1343 0 MVQXPV+UniversLTStd-Cn Type 1C Custom yes yes yes 1344 0 KSRLNZ+UniversLTStd-Bold Type 1C Custom yes yes yes 1345 0 IKSZLD+UniversLTStd-Obl Type 1C Custom yes yes yes 1360 0 GHONJH+UniversLTStd Type 1C Custom yes yes yes 1365 0 GHGPJH+GlyphaLTStd-Light Type 1C Custom yes yes yes 358 0 GlyphaLTStd-Bold2 Type 1C WinAnsi yes no yes 362 0 EEPBHL+GlyphaLTStd Type 1C Custom yes yes yes 378 0 GlyphaLTStd-Light2 Type 1C Custom yes no yes 372 0 GlyphaLTStd-Bold3 Type 1C Custom yes no yes 374 0 DFAVTN+MinionPro-Regular Type 1C WinAnsi yes yes yes 388 0 BCBJRR+Helvetica-Bold Type 1C WinAnsi yes yes no 391 0 BCBJRR+Helvetica Type 1C WinAnsi yes yes no 402 0 AYRDDT+Helvetica-Oblique Type 1C WinAnsi yes yes no 393 0 AYRDDT+Symbol Type 1C Custom yes yes no 405 0 AYRDDT+UniversLTStd-BoldCn Type 1C Custom yes yes yes 398 0 Helvetica2 Type 1C WinAnsi yes no no 409 0 Helvetica-Bold2 Type 1C WinAnsi yes no no 410 0 Helvetica3 Type 1C WinAnsi yes no no 411 0 Helvetica4 Type 1C WinAnsi yes no no 418 0 VTEZLD+UniversLTStd-CnObl Type 1C WinAnsi yes yes yes 415 0 Helvetica5 Type 1C WinAnsi yes no no 416 0 Helvetica-Bold3 Type 1C WinAnsi yes no no 417 0 Helvetica-Bold4 Type 1C WinAnsi yes no no 413 0 Helvetica-Bold5 Type 1C WinAnsi yes no no 412 0 Helvetica-Bold6 Type 1C WinAnsi yes no no 414 0 WSOFZB+Helvetica-BoldOblique Type 1C WinAnsi yes yes no 419 0 Helvetica-Bold7 Type 1C WinAnsi yes no no 420 0 UPPTXF+Helvetica-BoldOblique2 Type 1C WinAnsi yes yes no 422 0 UPPTXF+Helvetica6 Type 1C WinAnsi yes yes no 421 0 Helvetica-Bold8 Type 1C WinAnsi yes no no 423 0 TLANJH+Helvetica7 Type 1C WinAnsi yes yes no 424 0 Helvetica8 Type 1C WinAnsi yes no no 426 0 Helvetica-Bold9 Type 1C WinAnsi yes no no 425 0 SMQHVJ+Helvetica-Oblique2 Type 1C WinAnsi yes yes no 428 0 SMQHVJ+Helvetica-Narrow Type 1C WinAnsi yes yes no 427 0 SMQHVJ+UniversLTStd-LightCn Type 1C Custom yes yes yes 468 0 QJRVTN+UniversLTStd-LightCnObl Type 1C WinAnsi yes yes yes 466 0 OGNJRR+GandhariUnicode-Roman Type 1C Custom yes yes yes 469 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-01-14 02:29:58 CET RepresentationInformation: pmc_9653173.pdf ReportingModule: BYTESTREAM, Rel. 1.4 (2018-10-01) LastModified: 2022-11-24 02:13:38 CET Size: 647994 Format: bytestream Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/octet-stream Checksum: f5a40586 Type: CRC32 Checksum: 342f4593655845694bc8ead0e59827c2 Type: MD5 Checksum: 7892526b8e1ba3a98c4903cd352191a669e10704 Type: SHA-1