Trotabresib, an oral potent bromodomain and extraterminal inhibitor, in patients with high-grade gliomas: A phase I, “window-of-opportunity” study

Abstract

Background The bromodomain and extraterminal protein (BET) inhibitor trotabresib has demonstrated antitumor activity in patients with advanced solid tumors, including high-grade gliomas. CC-90010-GBM-001 (NCT04047303) is a phase I study investigating the pharmacokinetics, pharmacodynamics, and CNS penetration of trotabresib in patients with recurrent high-grade gliomas scheduled for salvage resection. Methods Patients received trotabresib 30 mg/day on days 1–4 before surgery, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off after surgery. Primary endpoints were plasma pharmacokinetics and trotabresib concentrations in resected tissue. Secondary and exploratory endpoints included safety, pharmacodynamics, and antitumor activity. Results Twenty patients received preoperative trotabresib and underwent resection with no delays or cancellations of surgery; 16 patients received maintenance trotabresib after recovery from surgery. Trotabresib plasma pharmacokinetics were consistent with previous data. Mean trotabresib brain tumor tissue:plasma ratio was 0.84 (estimated unbound partition coefficient [KPUU] 0.37), and modulation of pharmacodynamic markers was observed in blood and brain tumor tissue. Trotabresib was well tolerated; the most frequent grade 3/4 treatment-related adverse event during maintenance treatment was thrombocytopenia (5/16 patients). Sixmonth progression-free survival was 12%. Two patients remain on treatment with stable disease at cycles 25 and 30. Conclusions Trotabresib penetrates the blood–brain-tumor barrier in patients with recurrent high-grade glioma and demonstrates target engagement in resected tumor tissue. Plasma pharmacokinetics, blood pharmacodynamics, and safety were comparable with previous results for trotabresib in patients with advanced solid tumors. Investigation of adjuvant trotabresib + temozolomide and concomitant trotabresib + temozolomide + radiotherapy in patients with newly diagnosed glioblastoma is ongoing (NCT04324840).

BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas

“…These data suggest that trotabresib monotherapy may provide long-lasting disease control in some patients, and demonstrate the long-term efficacy and good tolerability of intermittent dosing of trotabresib even in patients with advanced, progressive disease. Importantly, the durable CR in a patient with progressive diffuse astrocytoma and the minor radiographic response in a patient with high-grade astrocytoma, a tumor type with typically poor outcomes and limited effective treatment options, illustrate the ability of trotabresib to penetrate brain tumor tissue 35 . Penetration of brain tumor tissue is a key challenge in the treatment of gliomas and other central nervous system tumors 36,37 .…”

“…The results reported here demonstrate the preliminary anticancer properties of trotabresib monotherapy across a range of heavily pretreated advanced solid tumors and in R/R DLBCL, supporting further investigation of its use in combination with other anticancer agents. Based on the responses observed in this study, a clinical trial has been initiated to investigate trotabresib in combination with temozolomide in patients with newly diagnosed glioblastoma (NCT04324840) 35,[49][50][51] .…”

Bromodomain and extraterminal protein-targeted probe enables tumour visualisation in vivo using positron emission tomography

“…BALB/c nu/nu ( n = 3) mice bearing U-87 MG subcutaneous tumours were orally administered a therapeutic dose of Trotabresib (25 mg kg −1 ) at 1.5 hours prior to PET imaging and compared to a cohort of non-blocked mice ( n = 3) bearing U-87 MG tumours (Phase I trials of Trotabresib have shown a median time to peak blood concentration of 1.5 hours in patients). 15 A reduction in tumour uptake was observed in cross-sectional PET images of mice pre-administered Trotabresib, relative to non-blocked mice (Fig. 4a and b).…”

“…14 Currently under Phase II clinical investigations for the treatment of advanced solid tumours (NCT03220347) and glioblastoma as a monotherapy (NCT04047303), and in combination with Temozolomide (NCT03220347) Trotabresib is distinguished from other BET inhibitors by its ability to penetrate the BBB. 15…”

“…14 Currently under Phase II clinical investigations for the treatment of advanced solid tumours (NCT03220347) and glioblastoma as a monotherapy (NCT04047303), and in combination with Temozolomide (NCT03220347) Trotabresib is distinguished from other BET inhibitors by its ability to penetrate the BBB. 15 Using Trotabresib as a structural platform, a set of fluorine-18 labelled BETi-based PET radiotracers for targeted imaging of cancer were designed: [ 18 F]BiPET-1, [ 18 F]BiPET-2, and [ 18 F]BiPET-3, (BET inhibitor PET radiotracer) (Fig. 1c).…”