Neuro-Oncology Advances 1 4(1), 1–11, 2022 | https://doi.org/10.1093/noajnl/vdac146 | Advance Access date 28 October 2022 Trotabresib (CC-90010) in combination with adjuvant temozolomide or concomitant temozolomide plus radiotherapy in patients with newly diagnosed glioblastoma    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,1 Bishoy Hanna, Ida Aronchik,1 Ellen Filvaroff, Henry Chang, Cristina Mendez, Marina Arias Parro, Xin Wei, Zariana Nikolova, Juan Manuel Sepulveda Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain (M.V.); Universidad Autonoma de Barcelona, Barcelona, Spain (M.V.); Department of Biomedical Sciences, Humanitas University, Milan, Italy (M.S.); IRCCS Humanitas Research Hospital, Milan, Italy (M.S., E.L.); Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (F.D.V.); START Madrid-FJD, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain (V.M.); Erasmus MC Cancer Institute, Rotterdam, the Netherlands (M.G., M.J.V.D.B., M.D.J.); Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy (M.M., G.D.C.); Neuro-Oncology Unit, Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain (M.C.M.S.); Centre for Innovation and Translational Research Europe, A Bristol Myers Squibb Company, Seville, Spain (B.A., T.S.P., C.M., Z.N.); Bristol Myers Squibb, San Francisco, CA, USA (M.Z., I.A., E.F., H.C.); Bristol Myers Squibb, Princeton, NJ, USA (B.H., X.W.); Bristol Myers Squibb, Boudry, Switzerland (M.A.P.); Hospital Universitario 12 de Octubre, Madrid, Spain (J.M.S.) 1At the time of the study. Corresponding Author: Maria Vieito, Vall d’Hebron Institute of Oncology (VHIO), Centro Cellex, Carrer de Natzaret, 115–117, 08035 Barcelona, Spain(mvieito@vhio.net) Abstract Background: Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery fol- lowed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; how- ever, 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 concomi- tant 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 prelim- inary efficacy and pharmacokinetics. Pharmacodynamics were investigated as an exploratory endpoint. Results: The adjuvant and concomitant cohorts enrolled 18 and 14 patients, respectively. Trotabresib in combi- nation 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, respec- tively, with 1 patient in the adjuvant cohort achieving complete response. © The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 2 Vieito et al. Trotabresib with TMZ ± RT in newly diagnosed GBM Conclusions: Trotabresib combined with TMZ in the adjuvant setting and with TMZ+RT in the concomi- tant 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. Key Points • Trotabresib combined with adjuvant TMZ or concomitant TMZ + RT was well tolerated. • TMZ and RT did not impact trotabresib pharmacokinetics or pharmacodynamics. • Preliminary efficacy with trotabresib + TMZ ± RT appeared encouraging. Importance of the Study Standard-of-care (SOC) therapy for newly weeks in the adjuvant and concomitant set- diagnosed glioblastoma (ndGBM) is maximal tings, respectively. Six-month progression-free surgical resection followed by concomitant survival rates were 57.8% and 69.2% in the ad- radiotherapy and temozolomide and adjuvant juvant and concomitant settings, respectively. temozolomide; however, prognosis remains The recommended phase II dose of trotabresib poor. Our study investigates trotabresib, a was established as 30 mg. Based on these re- novel, oral, reversible bromodomain and sults, patient enrollment has started for the ran- extraterminal inhibitor that penetrates the domized phase II dose expansion, which will blood–brain barrier, combined with adjuvant compare concomitant trotabresib 30 mg plus temozolomide and concomitant temozolomide temozolomide and radiotherapy followed by plus radiotherapy in patients with ndGBM. adjuvant trotabresib 30 mg plus temozolomide Trotabresib was well tolerated in both settings. then maintenance with trotabresib 45 mg Median duration of treatment was 33 and 34 monotherapy versus SOC. Glioblastoma, the most common and aggressive primary involved in oncogenesis, apoptosis, and cell cycle progres- brain tumor in adults, is challenging to treat and remains in- sion.9,10 BET proteins have been found to be overexpressed curable despite extensive research.1 Standard-of-care (SOC) in a range of tumor types, including glioblastoma, and el- therapy for newly diagnosed glioblastoma, consisting of evated levels of BRD2 and BRD4 are associated with poor maximal safe surgical resection followed by radiotherapy prognosis in patients with glioblastoma.10–14 BET inhibitors (RT) and concomitant temozolomide (TMZ), followed by ad- have been shown to regulate expression of key genes as- juvant TMZ, was established over 15 years ago.2 TMZ plus sociated with glioblastoma proliferation, including MYC, RT significantly improved survival compared with RT alone, CDKN1A, and BCL2L1, and to decrease glioblastoma cell with a hazard ratio for overall survival (OS) of 0.6 (95% CI: growth in vitro and in patient-derived xenograft (PDX) 0.5–0.7; P < .0001).3,4 However, the poor prognosis for pa- models.10,15,16 BET proteins are therefore relevant ther- tients with glioblastoma is highlighted by the low 6-month apeutic targets in cancer. Inhibition of BET proteins has progression-free survival (PFS) rate of 53.9% and 5-year demonstrated antitumor activity in clinical trials across a OS rate of 9.8% in patients receiving TMZ plus RT.3,4 A key range of advanced cancers,17–19 supporting investigation of contributor to poor outcomes is the high rate of recurrence BET inhibitors for the treatment of glioblastoma. However, due to extensive tumor infiltration of surrounding brain although preclinical studies of various BET inhibitors have tissue and the difficulty of achieving complete surgical re- shown antitumor effects in glioblastoma models (reviewed section.1,5,6 Clinical trials have found many otherwise prom- in Yang et al20), clinical investigation has been limited, with ising therapies to have minimal antitumor activity, with poor a dose-finding study of OTX015 in patients with glioblas- blood–brain barrier (BBB) penetration thought to be a key toma being discontinued due to lack of clinical activity contributing factor.7,8 Given the unmet medical needs of pa- after failing to meet its primary endpoint of 6-month PFS,21 tients with glioblastoma, new therapies with novel mechan- suggestive of poor BBB penetration in humans and/or isms of action and the ability to cross the BBB are urgently nonoptimal dosing. needed to improve patient outcomes. Trotabresib (CC-90010; BMS-986378) is a novel, oral, re- The bromodomain and extraterminal (BET) family of versible, small-molecule inhibitor of BET proteins. In the proteins, comprising BRD2, BRD3, BRD4, and BRDT, are ep- first-in-human CC-90010-ST-001 study, trotabresib dem- igenetic readers that regulate the expression of key genes onstrated encouraging antitumor activity across a range Vieito et al. Trotabresib with TMZ ± RT in newly diagnosed GBM 3 Advances Neuro-Oncology of doses and dosing schedules in patients with advanced for patients enrolled in the adjuvant and concomitant malignancies, including durable responses in patients with dose-escalation cohorts (part A). high-grade gliomas (V. Moreno, unpublished manuscript). In a “window-of-opportunity” phase I study, CC-90010- GBM-001, patients with recurrent high-grade glioma who were scheduled for salvage resection received trotabresib Materials and Methods 30 mg/day on days 1–4 before surgery, followed by main- tenance trotabresib monotherapy 45 mg administered Study Design on days 1–4 of each 28-day cycle (4 days on/24 days off) CC-90010-GBM-002 is a multicenter, open-label, phase Ib/ after surgery, with the aim of evaluating trotabresib BBB II, dose-finding study in adult patients with newly diag- penetration.22 The study found that trotabresib reached nosed glioblastoma. The phase Ib, dose-escalation part of detectable concentrations in resected contrast-enhancing this study explored escalating oral doses of trotabresib and non-enhancing brain tumor tissue, with a brain tumor in combination with TMZ in the adjuvant setting and with tissue:plasma ratio of 0.84. Trotabresib was well toler- TMZ plus RT in the concomitant setting. In the adjuvant ated, and 2 patients remained on treatment in cycles 19 setting, patients received 6 cycles of trotabresib adminis- and 23, with durable stable disease (SD) at the time of last tered at doses of 15, 30, and 45 mg 4 days on/24 days off follow-up.22 in combination with TMZ administered per label,33,34 fol- Preclinical studies have demonstrated that trotabresib lowed by trotabresib 45 mg 4 days on/24 days off as main- has antitumor activity in glioblastoma models as a single tenance therapy. After two dose-escalation levels were agent and enhances the antiproliferative effects of TMZ in assessed as safe and tolerable in the adjuvant therapy glioblastoma PDX models (Supplementary Figure S1). TMZ cohort, the concomitant therapy dose-escalation portion inhibits DNA replication through addition of alkyl groups was initiated, in which patients received 6 weeks of treat- to the O6 position of guanines. Importantly, expression of ment with trotabresib 15 or 30 mg, administered on days O6-methylguanine-DNA methyltransferase (MGMT), an en- 1–4 in weeks 1 and 5, in combination with concomitant zyme that removes alkyl groups from DNA, is associated TMZ and RT administered per label.33,34 After completion with decreased benefit from TMZ therapy, and methyla- of the concomitant treatment stage, patients had a 4-week tion of the MGMT promoter is associated with improved treatment break then received adjuvant trotabresib ad- OS in patients treated with TMZ.23–28 Preclinical studies in- ministered 4 days on/24 days off at the highest dose level dicate that trotabresib downregulates MGMT expression that was well tolerated by at least 1 cohort in the adjuvant in a dose-dependent manner (Supplementary Figure S2), dose escalation, plus TMZ administered per label, followed providing further support to the combination of trotabresib by maintenance trotabresib 45 mg administered 4 days and TMZ. Trotabresib has demonstrated antiproliferative on/24 days off. Dose-escalation decisions were made by activity as a single agent in glioblastoma PDX models, the safety review committee, based on all available safety, regardless of MGMT promoter methylation status; these pharmacokinetics, pharmacodynamics, and preliminary effects may be exerted by modulating the expression of efficacy information, and a calculation of risk assessment other genes, such as MYC. MYC is often overexpressed in using a Bayesian logistic regression model. The study de- glioblastoma29,30 and has been shown to be downregulated sign is shown in Figure 1. in vitro by trotabresib (Bristol Myers Squibb; data on file) and the BET inhibitor, JQ1.15 A rationale for combining BET inhibition with RT has Patient Selection been provided in preclinical studies. In rhabdomyosarcoma cells, OTX015 demonstrated antitumor activity as a single Eligible patients were ≥18 years of age, had newly diag- agent and, by downregulating drivers of cell proliferation nosed, histologically confirmed World Health Organization and resistance, potentiated the effects of ionizing radia- grade IV glioblastoma (2016 classification) and had under- tion.31 In breast cancer cells, iBET-762 upregulated expres- gone complete or partial tumor resection, and an Eastern sion of the HER2-regulated gene, TUBB3, and increased Cooperative Oncology Group performance status (ECOG sensitivity to vinorelbine in vitro and in PDX models. In a PS) of 0 or 1. Patients must not have had a requirement mouse model of breast cancer brain metastases, longer for ongoing treatment with therapeutic or prophylactic survival was observed in mice treated with iBET-762 com- anticoagulants. bined with vinorelbine plus radiation than in mice treated For enrollment in the adjuvant cohort, patients must with radiation alone, or iBET-762 or vinorelbine in combi- have recently completed a course of concomitant TMZ plus nation with radiation.32 standard or hypofractionated RT, with an MRI documenting CC-90010-GBM-002 (NCT04324840) is a phase Ib/II study SD prior to the first dose of trotabresib. For enrollment in in adult patients with newly diagnosed grade IV glioblas- the concomitant cohort, patients must have been eligible toma who have undergone complete or partial tumor for treatment with TMZ plus RT and have undergone com- resection. The study is investigating trotabresib in com- plete or partial tumor resection ≤8 weeks, but preferably ≤6 bination with TMZ in the adjuvant setting followed by weeks, prior to the first dose of trotabresib. maintenance trotabresib monotherapy, and trotabresib Key exclusion criteria were receipt of prior chemo- combined with TMZ and RT in the concomitant setting fol- therapy or other antitumor treatment for glioblastoma (ei- lowed by adjuvant trotabresib plus TMZ, followed by main- ther approved or investigational) except for surgery (and tenance trotabresib monotherapy. Here, we present safety, for patients in the adjuvant therapy cohort, mandatory pharmacokinetics, pharmacodynamics, and efficacy data concomitant TMZ plus RT). Patients were also excluded if 4 Vieito et al. Trotabresib with TMZ ± RT in newly diagnosed GBM    Adjuvant setting N = 18 Adjuvant treatment (28-day cycles) Inclusion criteria: Monotherapy Cycle 1 • Newly diagnosed GBM • Trotabresib 15, 30, or 45 mg Trotabresib 45 mg • Complete or partial resection 4 days on/24 days off 4 days on/24 days off until disease • ECOG PS 0–1 • TMZ 150 mg/m2 QD days 1–5 Primary endpoints: progression, start • Completed SOC therapy Cycles 2–6 of new anticancer • Safety and with RT + TMZ • Trotabresib 4 days on/24 days therapy, withdrawal tolerability • Confirmed SD prior to off (continue at current dose) of consent, or • MTD first dose of trotabresib • TMZ 200 mg/m2 QD days 1–5 investigator decision • RP2D (if well tolerated) Secondary endpoints: • PFS at 6 and 12 months • OS at 6 and Concomitant setting 12 months • Plasma pharmacokinetics N = 14 Adjuvant treatment Exploratory endpoints: Concomitant Monotherapy SOC break (4 weeks) (28-day cycles) • Pharmacodynamics Inclusion criteria: treatment (6 weeks) Cycle 1 Trotabresib 45 mg (blood CCR1 • Newly diagnosed GBM • Trotabresib 15 or 4 days on/24 days • Trotabresib 4 days on/24 days offa and HEXIM1 • Complete or partial 30 mg QD days 1–4 off until disease mRNA levels) resection ≤8 weeks prior in weeks 1 and 5 • TMZ 150 mg/m2 QD days 1–5 progression, start • Other biomarkers to first dose of trotabresib • RT2Gy QD Cycles 2–6 of new anticancer • ECOG PS 0–1 × 5 days/week therapy, withdrawal • Trotabresib 4 days on/24 days off of consent, or • SOC-eligible (60 Gy in 30 fractions) • TMZ 200 mg/m2 QD days 1–5 investigator decision • TMZ 75 mg/m2 QD (if well tolerated) Figure 1. CC-90010-GBM-002 study design. aAdministered at the highest dose level that was well tolerated by at least 1 cohort in the adjuvant dose escalation. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; GBM, glioblastoma; MTD, maximum tolerated dose; OS, overall survival; PFS, progression-free survival; QD, daily; RP2D, recommended phase II dose; RT, radiotherapy; RT2Gy, radiotherapy at 2 Gray per fraction; SD, stable disease; SOC, standard-of-care; TMZ, temozolomide.    they had any known metastatic extracranial or leptomenin- RT as concomitant therapy. Secondary endpoints included geal disease. assessment of preliminary efficacy in terms of PFS (de- Additional exclusion criteria included mild or asympto- fined as the time from randomization to the date of first matic SARS-CoV-2 infection within 10 days or severe/crit- documented tumor progression or death prior to imaging ical SARS-CoV-2 infection within 20 days prior to cycle 1, showing progression) and OS rates at 6 and 12 months day 1 (C1D1). Acute symptoms must have resolved, and and antitumor response, as well as the plasma pharmaco- based on investigator assessment in consultation with the kinetics of trotabresib. Trotabresib pharmacodynamics was medical monitor, there must be no sequelae that would an exploratory endpoint. place the patient at increased risk while receiving study Adverse events (AEs) were classified using the Medical treatment. Patients receiving previous SARS-CoV-2 vaccine Dictionary for Regulatory Activities v18.1 or higher system within 14 days prior to C1D1 were excluded; for vaccines organ class and preferred term. Severity of AEs was graded requiring more than 1 dose, the full series (e.g., both doses based on the patient’s symptoms according to the National of a 2-dose series) should have been completed prior to Cancer Institute Common Terminology Criteria for Adverse C1D1 when feasible and when a delay in C1D1 would not Events v5.0.35 Dose-limiting toxicities (DLTs) were defined put the patient at risk. The administration of a live SARS- as any of the toxicities described in Supplementary Table CoV-2 vaccine was prohibited up to 14 days prior to the ini- S2 occurring within the DLT assessment period (cycle 1 tiation of study treatment. [28 days]), unless the event could clearly be determined A full description of inclusion and exclusion criteria is to be unrelated to trotabresib. Screening MRI scans were provided in Supplementary Table S1. performed after surgical resection and within 28 days All patients provided written informed consent, and the (+3 days) prior to initiation of study treatment. Subsequent study was conducted in compliance with the International tumor assessments by MRI or CT were performed at week Council on Harmonisation of Technical Requirements for 10 during the concomitant treatment period and at the end Registration of Pharmaceuticals for Human Use, Good of every other treatment cycle from cycle 2 onwards during Clinical Practice, and general ethical principles outlined in the adjuvant and trotabresib monotherapy treatment the Declaration of Helsinki. periods. Best overall response (BOR) was evaluated as complete response (CR), partial response (PR), SD, progres- sive disease (PD), or not evaluable, according to Response Endpoints and Assessments Assessment in Neuro-Oncology criteria for high-grade The primary endpoints of the study were to determine the glioma.36 Plasma samples were collected during the first safety and tolerability, maximum tolerated dose, and/or re- treatment cycle for investigation of trotabresib pharmaco- commended phase II dose (RP2D) of trotabresib in com- kinetics and pharmacodynamics. Plasma pharmacokinetic bination with TMZ as adjuvant therapy, and with TMZ and parameters assessed included peak plasma concentration Vieito et al. Trotabresib with TMZ ± RT in newly diagnosed GBM 5 Advances Neuro-Oncology (Cmax), time to peak plasma concentration (tmax), area under    the plasma concentration–time curve (AUC), and terminal Table 1. Patient demographics and characteristics half-life (t½). Pharmacodynamic markers assessed included Patient characteristic Adjuvant overall Concomitant blood levels of CCR1 and HEXIM1 mRNA, which are estab- (N = 18) overall lished markers of BET inhibitor target engagement.17,22,37,38 (N = 14) Baseline isocitrate dehydrogenase (IDH) mutation status Median age (range), 53 (31–70) 56 (29–71) and MGMT promoter methylation status were determined years in surgically resected brain tumor tissue using recently Sex, n (%) obtained tissue from surgery and assessed per methodolo- gies adopted at each institution. Male 12 (67) 8 (57) The sample size was not based on strict statistical power Female 6 (33) 6 (43) calculations. Safety, efficacy, and pharmacodynamic ana- ECOG PS, n (%) lyses were summarized using descriptive statistics. Plasma 0 14 (78) 6 (43) pharmacokinetic parameters were calculated by the 1 4 (22) 8 (57) noncompartmental analysis method from plasma concen- tration–time profiles. Type of resection, n (%) Complete 10 (56) 9 (64) Partial 8 (44) 5 (36) Results MGMT promoter methylation status, n (%) Methylated 6 (33) 7 (50) Patients and Treatment Unmethylated 10 (56) 3 (21) Patient enrollment for part A was completed on July 5, Not reported 2 (11) 4 (29) 2021. Eighteen patients were enrolled in the adjuvant co- IDH mutation status, n (%) hort and received trotabresib 15 mg (n = 5), 30 mg (n = 6), Wild type 17 (94) 11 (79) or 45 mg (n = 7) 4 days on/24 days off plus TMZ. Fourteen Mutant 1 (6) 2 (14) patients were enrolled in the concomitant cohort and re- Not reported 0 1 (7) ceived trotabresib 15 mg (n = 6) or 30 mg (n = 8) 4 days on/24 days off plus TMZ and RT. Abbreviation: ECOG PS, Eastern Cooperative Oncology Group per- At the time of preparing this report (May 11, 2022), 5 formance status. (28%) patients in the adjuvant cohort and 6 (43%) patients in the concomitant cohort remained on treatment. In the    adjuvant cohort, 8 (44%) patients discontinued due to PD, 3 (17%) patients discontinued due to AEs, 1 (6%) patient discontinued due to investigator decision, and 1 (6%) pa- (56%) and 9 (64%) patients in the adjuvant and concom- tient discontinued due to radionecrosis. In the concomitant itant cohorts, respectively (Figure 2 and Supplementary cohort, 4 (29%) patients discontinued due to PD, 3 (21%) Table S3). patients withdrew consent, and 1 (7%) patient discon- In the overall adjuvant cohort, thrombocytopenia was tinued due to an AE. Among patients who withdrew con- the most common any-grade and grade 3/4 TRAE related sent, 1 withdrew due to the perceived burden of multiple to any study drug, reported in 13 (72%) and 9 (50%) pa- grade 1/2 AEs caused by study treatments, 1 lived far from tients, respectively (Figure 2A and Supplementary Table the institution and family members were unable to assist S3). Thrombocytopenia was attributed to trotabresib in with travel and domestic matters, and 1 preferred to pro- 10 (56%) and 7 (39%) patients at any grade and grade 3/4, ceed with off-protocol SOC therapy. Following treatment respectively. Gastrointestinal TRAEs related to any study discontinuation, 3 (17%) patients and 1 (7%) patient in the drug occurred frequently (reported in 14 [78%] patients); adjuvant and concomitant cohorts, respectively, died fol- however, grade 3/4 gastrointestinal TRAEs were reported lowing disease progression. in only 1 (6%) patient (diarrhea). Rash and other skin- Baseline demographics and characteristics are described related TRAEs were reported in 9 (50%) patients, all grade in Table 1. Median age was 53 and 56 years in the adjuvant 1 or 2, and were attributed to both trotabresib and TMZ in and concomitant cohorts, respectively. Twelve (67%) and 8 2 (11%) patients and to trotabresib only in 7 (39%) patients. (57%) patients were male in the adjuvant and concomitant In the overall concomitant cohort, nausea was the most cohorts, respectively. Fourteen (78%) and 6 (43%) patients common any-grade TRAE related to any study drug, re- had an ECOG PS of 0 in the adjuvant and concomitant co- ported in 11 (79%) patients, all grade 1 or 2, and was at- horts, respectively. tributed to trotabresib in 8 (57%) patients (Figure 2B and Supplementary Table S3). Any-grade thrombocytopenia was reported in 10 (71%) patients and was attributed to Safety trotabresib in 9 (64%) patients. Thrombocytopenia was the most common grade 3/4 TRAE, reported in 7 (50%) At the February 20, 2022, data cutoff, any-grade treatment- patients, and was attributed to trotabresib in 6 (43%) pa- related AEs (TRAEs) were reported in 17 (94%) and 14 tients. Gastrointestinal TRAEs related to any study drug (100%) patients in the overall adjuvant and concomitant occurred in 13 (93%) of patients at any grade, with a grade cohorts, respectively. Grade 3/4 TRAEs were reported in 10 3/4 TRAE reported in 1 (7%) patient (diarrhea). Rash and 6 Vieito et al. Trotabresib with TMZ ± RT in newly diagnosed GBM other skin-related TRAEs were reported in 7 (50%) patients, Pharmacokinetics all grade 1 or 2, and were attributed to both trotabresib and TMZ in 3 (21%) patients and to trotabresib only in 4 (29%) Preliminary trotabresib plasma pharmacokinetic data were patients. available for all 18 patients in the adjuvant setting and for The incidence of TRAEs attributed to TMZ is shown in 13 of 14 patients in the concomitant setting; 1 patient in the Supplementary Table S3, and the overall incidence of concomitant trotabresib 30-mg cohort did not have sam- TRAEs at each dose level in the adjuvant and concomitant ples available for pharmacokinetics analysis. Increases in cohorts is shown in Supplementary Table S4. trotabresib exposure were proportional to dose in both Serious TRAEs were reported in 3 (17%) patients and 1 treatment settings. Trotabresib tmax on day 4 was 0.5–4.0 h (7%) patient in the adjuvant and concomitant cohorts, re- and mean t½ was 74.2 h (standard deviation ± 27.2; Figure spectively. In the adjuvant cohort at the trotabresib 30 mg 3). Trotabresib plasma pharmacokinetics at the RP2D of 4 days on/24 days off dose level, serious neutropenia and 30 mg were similar across the adjuvant and concomitant thrombocytopenia, attributed to both trotabresib and TMZ, settings, and were consistent with the pharmacokinetics of were reported in 1 patient, and serious intracranial hemor- trotabresib monotherapy,17,22,37 suggesting that trotabresib rhage, attributed to trotabresib, was reported in 1 patient. plasma pharmacokinetics were not affected by TMZ or RT. Serious diarrhea, attributed to trotabresib, was reported in 1 patient who received trotabresib 45 mg 4 days on/24 days off in the adjuvant cohort. Serious bone marrow failure, Pharmacodynamics attributed to both trotabresib and TMZ, was reported in 1 In patients receiving trotabresib at the RP2D of 30 mg in patient in the concomitant cohort who was treated at the the adjuvant and concomitant settings, blood pharmaco- trotabresib 30 mg 4 days on/24 days off dose level. There dynamics were consistent with those observed in clinical were no treatment-related deaths. trials investigating trotabresib monotherapy.17,22,37 On day In the adjuvant cohort, 2 (11%) patients permanently dis- 4, expression of blood CCR1 mRNA at 2–4 h post-dose was continued trotabresib and TMZ due to treatment-emergent ≥50% lower than at baseline in both the adjuvant and con- AEs (TEAEs) considered unrelated to treatment in 1 patient comitant settings. Similar CCR1 modulation was observed at the 45-mg dose level and related to both trotabresib and in patients treated with trotabresib 45 mg in the adju- TMZ in 1 patient at the 30-mg dose level. No TEAEs leading vant cohort, but no decrease in CCR1 expression was ob- to discontinuation of either study drug were reported in served in patients treated with trotabresib 15 mg in either the concomitant cohort (Supplementary Table S5). One pa- the adjuvant or concomitant cohorts. At the RP2D, CCR1 tient in the 30-mg adjuvant cohort discontinued treatment mRNA expression returned to baseline levels by 168 h due to a DLT of thrombocytopenia. Details of treatment post-dose in cycle 1 (Figure 4A). At the RP2D in the adju- duration and relative dose intensities for trotabresib and vant and concomitant cohorts, a 2.5- to 4.0-fold increase in TMZ are shown in Supplementary Table S6. The RP2D of blood HEXIM1 mRNA expression was observed on days 3 trotabresib was established as 30 mg in the adjuvant and and 4; HEXIM1 mRNA expression remained above base- concomitant settings. line until 168 h post-dose in cycle 1. HEXIM1 modulation    A Adjuvant B Concomitant Grade 3/4 Any grade Grade 3/4 Any grade Any TRAE Any TRAE Nausea Nausea Thrombocytopenia Thrombocytopenia Vomiting Vomiting Dysgeusia Dysgeusia Diarrhea Diarrhea Decreased appetite Decreased appetite Asthenia Asthenia Neutropenia Neutropenia Hyperbilirubinemia Hyperbilirubinemia Anemia Anemia Grade Fatigue Fatigue 3/4 Any Relationship Rash Rash Acneiform dermatitis Acneiform dermatitis Any study drug Dyspepsia Dyspepsia Hyperglycemia Hyperglycemia Trotabresib Lymphopenia Lymphopenia TMZ Pruritus Pruritus Leukopenia Leukopenia AST increased AST increased Hypophosphatemia Hypophosphatemia ALT increased ALT increased Hypotension Hypotension Insomnia Insomnia Seizure Seizure Blood bilirubin increased Blood bilirubin increased Intracranial hemorrhage Intracranial hemorrhage 100 80 60 40 20 0 20 40 60 80 100 100 80 60 40 20 0 20 40 60 80 100 Patients, % Patients, % Figure 2. TRAEs reported in ≥2 patients at any grade or in ≥1 patient at grade 3/4 severity in the (A) adjuvant and (B) concomitant cohorts by relationship to study drug. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; TMZ, temozolomide; TRAE, treatment- related adverse event.    Vieito et al. Trotabresib with TMZ ± RT in newly diagnosed GBM 7 Advances Neuro-Oncology increased with trotabresib dose in both cohorts (Figure At the time of preparing this report (May 11, 2022), 5 4B) and showed an association with time-matched (28%) and 6 (43%) patients in the adjuvant and concomi- trotabresib plasma concentrations in an exposure–re- tant cohorts, respectively, remained on treatment. Across sponse analysis using pooled data from the current study both cohorts, all ongoing patients have completed 6 and 2 other trotabresib studies, CC-90010-GBM-001 and cycles of adjuvant trotabresib plus TMZ and are receiving CC-90010-ST-001 (Supplementary Figure S3). trotabresib monotherapy, including 1 patient in the adju- vant trotabresib 15-mg cohort with an ongoing CR who has been on study treatment for 79 weeks and 1 patient with an Efficacy ongoing PR in the concomitant trotabresib 30-mg cohort who has been on study treatment for 51 weeks (Figure 5). At the February 20, 2022, data cutoff, median duration of treatment was 33 weeks (range: 4–72) in the adju- vant cohort and 34 weeks (range: 8–54) in the concomi- tant cohort. Median PFS was 7.6 months (95% CI: 3.9–not Discussion estimable [NE]) in the adjuvant cohort and NE (95% CI: 5.2 months–NE) in the concomitant cohort. PFS rate at Trotabresib, a next-generation BET inhibitor, has demon- 6 months was 57.8% (95% CI: 31.1–77.3) in the adjuvant strated encouraging antitumor activity as a single agent in cohort and 69.2% (95% CI: 37.3–87.2) in the concomi- preclinical models of glioblastoma and has previously been tant cohort (Supplementary Table S7). BOR for patients shown to penetrate the BBB and have durable antitumor in the adjuvant and concomitant cohorts is shown in activity in patients with high-grade gliomas (V. Moreno, un- Supplementary Table S8. published manuscript).22 In this study, trotabresib was well    Adjuvant trotabresib 15 mg + TMZ Adjuvant trotabresib 30 mg + TMZ Adjuvant trotabresib 45 mg + TMZ concentration, ng/mL (±SD) Mean trotabresib plasma 1500 Day 1 1500 Day 1 1500 Day 1 Day 4 Day 4 Day 4 1250 1250 1250 1000 1000 1000 750 750 750 500 500 500 250 250 250 0 0 0 0 2 4 24 0 2 4 24 0 2 4 24 Time (hours) Time (hours) Time (hours) Concomitant trotabresib 15 mg Concomitant trotabresib 30 mg + TMZ + RT + TMZ + RT concentration, ng/mL (±SD) Mean trotabresib plasma 1500 Day 1 1500 Day 1 Day 4 Day 4 1250 1250 1000 1000 750 750 500 500 250 250 0 0 0 2 4 24 0 2 4 24 Time (hours) Time (hours) Adjuvant trotabresib Adjuvant trotabresib Adjuvant trotabresib Concomitant trotabresib Concomitant trotabresib 15 mg + TMZ 30 mg + TMZ 45 mg + TMZ 15 mg + TMZ + RT 30 mg + TMZ + RT Plasma (n = 5) (n = 6) (n = 7) (n = 6) (n = 7) pharmacokinetic parameter Day 1 Day 4 Day 1 Day 4 Day 1 Day 4 Day 1 Day 4 Day 1 Day 4 AUC24, ng/h/mL, GM 2344 (14) 6621 (21) 4800 (27) 13 812 (24) 7025 (14) 19 988 (11) 2242 (2) 7025 (27) 4987 (30) 13 918 (23) (GCV%) Cmax, ng/mL, GM 201 (37) 433 (16) 306 (56) 822 (27) 522 (36) 1164 (21) 167 (36) 383 (28) 309 (20) 874 (28) (GCV%) tmax, h, median 1.0 1.5 2.0 1.5 2.0 1.5 2.0 1.3 2.0 1.5 (range) (0.5–2.0) (0.5–2.0) (1.5–4.0) (1.5–2.0) (1.0–24.0) (0.5–4.0) (1.0–24.0) (1.0–1.5) (1.5–4.0) (1.0–1.5) Figure 3. Trotabresib plasma pharmacokinetics. Abbreviations: AUC24, area under the trotabresib concentration–time curve from 0 to 24 hours; Cmax, peak trotabresib concentration; GCV, geometric coefficient of variation; GM, geometric mean; RT, radiotherapy; SD, standard deviation; tmax, time to peak trotabresib concentration; TMZ, temozolomide.    8 Vieito et al. Trotabresib with TMZ ± RT in newly diagnosed GBM    A CCR1 B HEXIM1 Adjuvant trotabresib Concomitant trotabresib Adjuvant trotabresib Concomitant trotabresib + TMZ + TMZ + RT + TMZ + TMZ + RT 15 mg (n = 5) 15 mg (n = 6) 15 mg (n = 5) 15 mg (n = 5) 350 350 600 600 300 300 Percentage of baseline Percentage of baseline 500 500 HEXIM1 expression CCR1 expression 250 250 400 400 200 200 150 150 300 300 100 100 200 200 50 50 100 100 0 0 50 50 –25 –25 0 0 0 24 48 72 96 120144168 0 24 48 72 96 120144168 0 24 48 72 96 120144168 0 24 48 72 96 120144168 Time after first dose (hours) Time after first dose (hours) 30 mg (n = 6) 30 mg (n = 8) 30 mg (n = 6) 30 mg (n = 8) 350 350 600 600 300 300 Percentage of baseline Percentage of baseline 500 500 HEXIM1 expression CCR1 expression 250 250 400 400 200 200 150 150 300 300 100 100 200 200 50 50 100 100 0 0 50 50 –25 –25 0 0 0 24 48 72 96 120144168 0 24 48 72 96 120144168 0 24 48 72 96 120144168 0 24 48 72 96 120144168 Time after first dose (hours) Time after first dose (hours) 45 mg (n = 7) 45 mg (n = 7) 350 600 300 Percentage of baseline Percentage of baseline 500 HEXIM1 expression CCR1 expression 250 400 200 150 300 100 200 50 100 0 50 –25 0 0 24 48 72 96 120144168 0 24 48 72 96 120144168 Time after first dose (hours) Time after first dose (hours) Figure 4. Trotabresib pharmacodynamics: modulation of (A) CCR1 and (B) HEXIM1 mRNA in blood. Abbreviations: RT, radiotherapy; TMZ, temozolomide.    tolerated in combination with TMZ in the adjuvant setting treatment-related thrombocytopenia was reported in 50% and with TMZ plus RT in the concomitant setting, with a of patients in both cohorts, while grade 3/4 neutropenia safety profile consistent with studies of trotabresib mono- was reported in 22% and 29% of patients in the adjuvant therapy and adjuvant TMZ (V. Moreno, unpublished man- and concomitant cohorts, respectively. Most frequently uscript).17,33,34 Gastrointestinal and hematological TRAEs occurring TRAEs were attributed to both study drugs, with were the most frequently reported across both cohorts. the exception of rash and other skin-related TRAEs. A se- Nearly all gastrointestinal TRAEs were reported at grade rious TRAE leading to discontinuation of both study drugs 1/2 severity, with grade 3/4 diarrhea reported in 1 patient (thrombocytopenia) was reported in 1 patient in the ad- who received trotabresib 45 mg in the adjuvant setting juvant cohort and was attributed to both trotabresib and and in 1 patient who received trotabresib 30 mg in the con- TMZ. No other serious TRAEs or TRAEs leading to discon- comitant setting. The hematological TRAEs thrombocyto- tinuation were reported. penia and neutropenia were the most frequently reported At the February 20, 2022, data cutoff, median duration grade 3/4 TRAEs in both treatment cohorts. Grade 3/4 of treatment was 33 weeks (range: 4–72) and 34 weeks Vieito et al. Trotabresib with TMZ ± RT in newly diagnosed GBM 9 Advances Neuro-Oncology    A Adjuvant trotrabresib plus TMZ B Concomitant trotrabresib plus TMZ and RT MGMT MGMT promoter IDH promoter IDH methylation mutation methylation mutation status status status status Treatment ongoing M WT NR WT NR WT CR 15 mg U WT PR U WT 15 mg U WT M WT SD U WT M WT Trotabresib dose Trotabresib dose NR WT Reason for treatment NR WT U WT discontinuation U NR 30 mg U WT Disease progression M WT M WT M WT TRAE M WT M WT Othera NR Mutant M WT Death U WT 30 mg U WT U Mutant M WT 45 mg U WT NR Mutant U WT U WT M WT M WT M WT 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 SOC break Adjuvant Concomitant Adjuvant Monotherapy Monotherapy therapy therapy therapy Duration of treatment, weeks Duration of treatment, weeks Figure 5. Treatment duration and response in the (A) adjuvant cohort and (B) concomitant cohort as of May 11, 2022. aIncludes withdrawal of consent and discontinuation due to TEAE or investigator decision. Abbreviations: CR, complete response; M, methylated; NR, not reported; PR, par- tial response; RT, radiotherapy; SD, stable disease; SOC, standard-of-care; TEAE, treatment-emergent adverse event; TMZ, temozolomide; TRAE, treatment-related adverse event; U, unmethylated; WT, wild type.    (range: 8–54) in the adjuvant and concomitant settings, investigating trotabresib monotherapy, indicating that respectively, which is indicative of promising preliminary coadministration with RT and TMZ did not appear to efficacy. However, survival data are not yet mature, with impact trotabresib pharmacokinetics.17,22,37 Trotabresib median PFS of 7.6 months (95% CI: 3.9–NE) in the adjuvant blood pharmacodynamics were consistent with data from cohort and NE (95% CI: 5.2 months–NE) in the concomitant studies investigating trotabresib monotherapy.17,22,37 cohort. PFS rate at 6 months was 57.8% (95% CI: 31.1–77.3) In patients receiving trotabresib at the RP2D of 30 mg, in the adjuvant setting and 69.2% (95% CI: 37.3–87.2) in blood CCR1 mRNA expression at 2–4 hours after the the concomitant setting. A previous study has shown that fourth dose of trotabresib was ≥50% lower than at base- patients treated with SOC TMZ + RT had a median PFS of line in the adjuvant and concomitant settings, which is 6.9 months (95% CI: 5.8–8.2), with a PFS rate at 6 months a reduction that has previously been shown to be asso- of 53.9% (95% CI: 48.1–59.6).3 However, it is important to ciated with response in patients with lymphoma treated note that only 84% of patients in that study had undergone with the BET inhibitor CPI-0610.39 Blood HEXIM1 mRNA partial or complete resection, with the remaining patients was increased 2.5- to 4.0-fold following the fourth dose having tumor biopsies only, whereas all patients included of trotabresib administered at the RP2D in both settings. in our study had undergone partial or complete resection At 168 hours post-dose in cycle 1, CCR1 mRNA expres- prior to receiving study treatment. Furthermore, 94% and sion returned to baseline and HEXIM1 mRNA expres- 79% of patients in the adjuvant and concomitant cohorts sion remained above baseline in patients treated with of our study, respectively, had wild-type IDH, and 50% of trotabresib at the RP2D in both settings. It is not known patients in the concomitant cohort had methylated MGMT when HEXIM1 mRNA expression returned to baseline be- promoters, both of which are factors associated with a cause patients did not undergo pharmacodynamic sam- more favorable prognosis. Taken together, these factors pling beyond 168 h. However, an exposure–response may provide an explanation for at least some of the ob- analysis using pooled data from the current study and 2 served efficacy and highlight the need for caution when other trotabresib studies, found a relationship between comparing results with those of previous studies. time-matched trotabresib plasma concentrations and At the time of preparing this report (May 11, 2022), 5 HEXIM1 mRNA expression. Blood pharmacodynamics (28%) patients in the adjuvant cohort remained on treat- of trotabresib were consistent with its long t½ of ~74 ment, including 1 patient at the trotabresib 15-mg dose hours, which correlates with the observed accumulation level with an ongoing CR who has been on study treatment of trotabresib in the blood. While HEXIM1 mRNA expres- for 79 weeks. In the concomitant cohort, 6 (43%) patients sion appeared to be returning towards baseline at 168 remain on treatment, of whom all have completed adju- hours post-dose, this could be explained by the >75% re- vant trotabresib plus TMZ and are receiving trotabresib duction in plasma trotabresib concentration at this time monotherapy, including 1 patient at the trotabresib 30-mg point, assuming a direct relationship between HEXIM1 dose level with an ongoing PR who has been on treatment expression and trotabresib exposures. for 51 weeks. Blood pharmacodynamic data from the adjuvant co- In this study, trotabresib plasma pharmacoki- hort showed that the increase in expression of blood netics were similar to those observed in clinical trials HEXIM1 mRNA was greater between trotabresib doses of 10 Vieito et al. Trotabresib with TMZ ± RT in newly diagnosed GBM 15 and 30 mg than between 30 and 45 mg. Furthermore, data from CC-90010-GBM-001 have demonstrated that Conflict of Interest Statement. M.V. and M.S. have no conflicts trotabresib at a dose of 30 mg results in sufficient expos- of interest to declare. F.D.V. has received research funding for ures to drive BBB penetration, with the study showing sponsor-driven trials by AbbVie, BioClin Therapeutics, Bristol measurable concentrations and modulation of phar- Myers Squibb, EORTC, Novartis, and VAXIMM and has re- macodynamic markers of target engagement in brain ceived research grants from Foundation STOPbraintumors.org. tumor tissue.22 Importantly, the trotabresib 30 mg 4 days V.M. has received consulting fees from Basilea, Bayer, Bristol on/24 days off dosing schedule was sufficient to induce Myers Squibb, Janssen, and Roche and has received prin- BET inhibition, as determined by blood CCR1 expression, cipal investigator institutional funding from AbbVie, ACEA Bio, while maintaining platelet nadir >100,000/mm3. At a dose Adaptimmune, ADC Therapeutics, Aduro, Agenus, amcure, of 45 mg, trotabresib may pose a higher risk of thrombo- Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BioInvent cytopenia and have the potential to impact SOC therapy International AB, Bristol Myers Squibb, Boehringer, Boston, by requiring TMZ dose reductions and/or preventing Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Therapeutics, TMZ dose escalation (Bristol Myers Squibb; data on file). Exelixis, Forma Therapeutics, Genmab, GSK, Harpoon, Consequently, the RP2D of trotabresib in combination Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa with TMZ in the adjuvant setting and with TMZ plus RT Kirin, Lilly, Loxo Oncology, MEDSIR, Menarini, Merck, Merus, in the concomitant setting was determined to be 30 mg Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate 4 days on/24 days off. Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, In conclusion, the RP2D of trotabresib in combination Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, with TMZ in the adjuvant setting and with TMZ plus RT Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, in the concomitant setting was determined to be 30 mg and Upsher-Smith. M.G., E.L., and M.M. have no conflicts of 4 days on/24 days off. Adjuvant trotabresib plus TMZ and interest to declare. M.J.V.D.B. has received honoraria from concomitant trotabresib plus TMZ and RT appeared to be AstraZeneca, Boehringer, Carthera, Chimerix, Genenta, and well tolerated, with encouraging preliminary efficacy sup- Nerviano. G.D.C., M.D.J., and M.C.M.S. have no conflicts of portive of further investigation. The pharmacokinetic pro- interest to declare. B.A., T.S.P., C.M., and Z.N. are employed file of trotabresib was consistent with studies investigating by Centre for Innovation and Translational Research Europe, trotabresib monotherapy, as were trotabresib pharmaco- a Bristol Myers Squibb Company. B.H., E.F., H.C., M.A.P., and dynamics, which demonstrated target engagement in pa- X.W. are employed by Bristol Myers Squibb. T.S.P., M.Z., B.H., tients with newly diagnosed glioblastoma. Based on these E.F., H.C., C.M., M.A.P., X.W., and Z.N. hold Bristol Myers Squibb results, a randomized phase II dose expansion (part B) with stock. J.M.S. has received research funding from IDP Pharma a planned enrollment of 162 patients has started, and will and Pfizer and has received consulting fees from GSK, MSD, compare concomitant trotabresib 30 mg plus TMZ and RT and UCB Pharma. I.A. and M.Z. were employed by Bristol Myers followed by adjuvant trotabresib 30 mg plus TMZ, followed Squibb at the time of the study. by maintenance with trotabresib 45 mg monotherapy versus SOC therapy. Authorship statement Key words Conception and design: Z.N., M.V., V.M., J.M.S. Patient re- trotabresib | BET inhibitors | glioblastoma | temozolomide | cruitment: M.V., M.S., F.D.V., V.M., M.G., E.L., M.M., M.J.V.D.B., pharmacokinetics. G.D.C., M.D.J., M.C.M.S., J.M.S. Data analysis and interpre- tation: All authors. Drafting and critical review of the manu- script: All authors. Acknowledgments The authors thank the patients and their families who made this Unpublished Papers study possible and the clinical study teams who participated in the study. This study was sponsored by Celgene, a Bristol Myers V. Moreno. Manuscript submitted to Neuro-Oncology. Squibb company. Medical writing and editorial assistance were provided by David Buist, PhD, and Matthew Weddig, BA, of Spark, funded by Bristol Myers Squibb. References Funding 1. King JL, Benhabbour SR. Glioblastoma multiforme-A look at the past and a glance at the future. Pharmaceutics 2021;13(7):1053. This study was sponsored by Celgene, a Bristol Myers Squibb 2. Weller M, van den Bent M, Preusser M, et al. EANO guidelines on the company. diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021;18(3):170–186. Vieito et al. Trotabresib with TMZ ± RT in newly diagnosed GBM 11 Advances Neuro-Oncology 3. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus con- “window of opportunity” study [abstract]. Neuro Oncol. 2021;23(Suppl comitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 6):CTNI–CT16. 2005;352(10):987–996. 23. Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA- 4. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with con- repair gene MGMT and the clinical response of gliomas to alkylating comitant and adjuvant temozolomide versus radiotherapy alone on sur- agents. N Engl J Med. 2000;343(19):1350–1354. vival in glioblastoma in a randomised phase III study: 5-year analysis of 24. Hegi ME, Diserens A-C, Gorlia T, et al. MGMT gene silencing the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–466. and benefit from temozolomide in glioblastoma. N Engl J Med. 5. Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treat- 2005;352(10):997–1003. ment of recurrent glioblastoma--are we there yet? Neuro Oncol 25. Hegi ME, Diserens A-C, Godard S, et al. Clinical trial substantiates the 2013;15(1):4–27. predictive value of O-6-methylguanine-DNA methyltransferase pro- 6. Tunthanathip T, Madteng S. Factors associated with the extent of resec- moter methylation in glioblastoma patients treated with temozolomide. tion of glioblastoma. Precis Cancer Med. 2020;3:12–12. Clin Cancer Res. 2004;10(6):1871–1874. 7. Sarkaria JN, Hu LS, Parney IF, et al. Is the blood–brain barrier really dis- 26. Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone rupted in all glioblastomas? A critical assessment of existing clinical versus radiotherapy alone for malignant astrocytoma in the elderly: the data. Neuro Oncol. 2017;20(2):184–191. NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13(7):707–715. 8. Pitz MW, Desai A, Grossman SA, Blakeley JO. Tissue concentration of 27. Malmström A, Grønberg BH, Marosi C, et al. Temozolomide versus systemically administered antineoplastic agents in human brain tumors. standard 6-week radiotherapy versus hypofractionated radiotherapy in J Neurooncol. 2011;104(3):629–638. patients older than 60 years with glioblastoma: the Nordic randomised, 9. Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET phase 3 trial. Lancet Oncol. 2012;13(9):916–926. bromodomain inhibition. Mol Cell. 2014;54(5):728–736. 28. Perry JR, Laperriere N, O’Callaghan CJ, et al. Short-course radiation 10. Pastori C, Daniel M, Penas C, et al. BET bromodomain pro- plus temozolomide in elderly patients with glioblastoma. N Engl J Med. teins are required for glioblastoma cell proliferation. Epigenetics. 2017;376(11):1027–1037. 2014;9(4):611–620. 29. Herms JW, von Loewenich FD, Behnke J, Markakis E, Kretzschmar HA. 11. Xu L, Chen Y, Mayakonda A, et al. Targetable BET proteins- and E2F1- c-myc oncogene family expression in glioblastoma and survival. Surg dependent transcriptional program maintains the malignancy of glio- Neurol. 1999;51(5):536–542. blastoma. Proc Natl Acad Sci USA. 2018;115(22):E5086–E5095. 30. Faria MH, Khayat AS, Burbano RR, Rabenhorst SH. c -MYC ampli- 12. Sun H-Y, Du S-T, Li Y-Y, Deng G-T, Zeng F-R. Bromodomain and extra- fication and expression in astrocytic tumors. Acta Neuropathol. terminal inhibitors emerge as potential therapeutic avenues for gastro- 2008;116(1):87–95. intestinal cancers. World J Gastrointest Oncol. 2022;14(1):75–89. 31. Camero S, Camicia L, Marampon F, et al. BET inhibition therapy counter- 13. Rhyasen GW, Yao Y, Zhang J, et al. BRD4 amplification facilitates an acts cancer cell survival, clonogenic potential and radioresistance mech- oncogenic gene expression program in high-grade serous ovarian cancer anisms in rhabdomyosarcoma cells. Cancer Lett. 2020;479:71–88. and confers sensitivity to BET inhibitors. PLoS One. 2018;13(7):e0200826. 32. Kanojia D, Panek WK, Cordero A, et al. BET inhibition increases βIII- 14. Segura MF, Fontanals-Cirera B, Gaziel-Sovran A, et al. BRD4 sustains tubulin expression and sensitizes metastatic breast cancer in the brain melanoma proliferation and represents a new target for epigenetic to vinorelbine. Sci Transl Med. 2020;12(558):eaax2879. therapy. Cancer Res. 2013;73(20):6264–6276. 33. Merck & Co Inc. (2015) TEMODAR® (temozolomide) [package insert]. 15. Cheng Z, Gong Y, Ma Y, et al. Inhibition of BET bromodomain targets ge- Available at: https://www.accessdata.fda.gov/drugsatfda_docs/ netically diverse glioblastoma. Clin Cancer Res. 2013;19(7):1748–1759. label/2016/021029s031lbl.pdf. Accessed December 1, 2021. 16. Berenguer-Daizé C, Astorgues-Xerri L, Odore E, et al. OTX015 (MK-8628), 34. Merck Sharp & Dohme B.V. (2022) TEMODAL® (temozolomide) [Summary a novel BET inhibitor, displays in vitro and in vivo antitumor effects alone of Product Characteristics]. Available at: https://www.ema.europa.eu/ and in combination with conventional therapies in glioblastoma models. en/medicines/human/EPAR/temodal. Accessed March 04, 2022. Int J Cancer. 2016;139(9):2047–2055. 35. US Department of Health and Human Services, National Institutes 17. Moreno V, Sepulveda JM, Vieito M, et al. Phase I study of CC-90010, of Health, National Cancer Institute. (2017) Common Terminology a reversible, oral BET inhibitor in patients with advanced solid tu- Criteria for Adverse Events (CTCAE) version 5.0. Available at: https:// mors and relapsed/refractory non-Hodgkin’s lymphoma. Ann Oncol. ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ 2020;31(6):780–788. CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed June 22, 2021. 18. Lewin J, Soria J-C, Stathis A, et al. Phase Ib trial with birabresib, 36. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assess- a small-molecule inhibitor of bromodomain and extraterminal pro- ment criteria for high-grade gliomas: response assessment in Neuro- teins, in patients with selected advanced solid tumors. J Clin Oncol. Oncology Working Group. J Clin Oncol. 2010;28(11):1963–1972. 2018;36(30):3007–3014. 37. Moreno V, Vieito Villar M, Sepulveda Sanchez JM, et al. CC-90010, 19. Piha-Paul SA, Hann CL, French CA, et al. Phase 1 study of molibresib a reversible, potent oral bromodomain and extraterminal inhibitor (GSK525762), a bromodomain and extra-terminal domain protein in- in patients with advanced solid tumors and relapsed/refractory dif- hibitor, in NUT carcinoma and other solid tumors. JNCI Cancer Spectr. fuse large B cell lymphoma: longer follow-up from parts A & B and 2020;4(2):pkz093. first reporting of part C of a phase 1 study. Ann Oncol. 2021;32(suppl 20. Yang H, Wei L, Xun Y, Yang A, You H. BRD4: an emerging prospective 1):Abstract 8MO. therapeutic target in glioma. Mol Ther Oncolytics. 2021;21:1–14. 38. Lin X, Huang X, Uziel T, et al. HEXIM1 as a robust pharmacodynamic 21. Hottinger AF, Sanson M, Moyal E, et al. Dose optimization of MK-8628 marker for monitoring target engagement of BET family bromodomain (OTX015), a small molecule inhibitor of bromodomain and extra-terminal inhibitors in tumors and surrogate tissues. Mol Cancer Ther. (BET) proteins, in patients (pts) with recurrent glioblastoma (GB). J Clin 2017;16(2):388–396. Oncol. 2016;34(suppl 15):e14123–e14123. 39. Abramson JS, Blum KA, Flinn IW, et al. BET inhibitor CPI-0610 is well 22. Vogelbaum MA, Sepulveda JM, Reardon D, et al. Trotabresib (CC-90010, tolerated and induces responses in diffuse large B-cell lymphoma and BMS-986378), a reversible, potent oral bromodomain and extraterminal follicular lymphoma: preliminary analysis of an ongoing phase 1 study. inhibitor (BETi) in patients with high-grade gliomas: a phase 1 open-label Blood. 2015;126(23):1491.