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).
Background
Standardofcare 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 treatmentrelated 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 followup, 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.
Trotabresib, a novel bromodomain and extraterminal protein inhibitor, has demonstrated antitumor activity and blood–brain barrier penetration in patients with high-grade gliomas, and enhanced the antiproliferative effects of temozolomide in preclinical models. CC-90010-GBM-002 (NCT04324840) is a phase 1b/2 study investigating the addition of trotabresib to standard-of-care (SOC) concomitant temozolomide plus radiotherapy and adjuvant temozolomide, followed by maintenance trotabresib, in patients with newly diagnosed glioblastoma. The design of the dose escalation (part A) has been described previously (Vieito M, et al. SNO 2021. Abstract CTNI-51). Primary objectives of part A were to establish the safety, tolerability, and maximum tolerated dose/recommended phase 2 dose (RP2D) of trotabresib. In part A, addition of trotabresib to SOC was safe and well tolerated in the concomitant (N = 14) and adjuvant (N = 18) cohorts; the most frequent grade 3/4 treatment-related adverse event was thrombocytopenia (7/14 and 9/18 patients, respectively). The RP2D for trotabresib was 30 mg/day 4 days on/24 days off in both settings. At data cutoff (February 20, 2022), median duration of treatment was 34 weeks (concomitant cohort) and 33 weeks (adjuvant cohort); progression-free survival data are not yet mature. Trotabresib plasma pharmacokinetics and pharmacodynamics were consistent with monotherapy. At last follow-up, 6 and 5 patients remained on treatment in the concomitant and adjuvant dose-escalation cohorts, respectively, including 1 patient in cycle 20 with ongoing complete response. The ongoing randomized phase 2 dose expansion (part B; planned N = 162) is comparing concomitant trotabresib at the RP2D + SOC followed by adjuvant trotabresib at the RP2D + SOC, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off, versus SOC alone in patients with newly diagnosed IDH–wild-type glioblastoma. Key objectives are to compare progression-free and overall survival, safety, and tolerability. Longer follow-up from part A and the first disclosure of data from part B will be presented.
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