The PI3K/AKT/mTOR pathway activation plays a central role in glioblastoma multiforme (GBM) development and progression, and in resistance to anti-cancer therapies. Inhibition of the PI3K pathway has been shown to sensitize cultured glioma cells and tumor xenografts to the effects of temozolomide (TMZ) and radiation. Vistusertib is an oral inhibitor of mTORC1/2 complexes. The primary objective of this Canadian Cancer Trials Group phase I study was to determine the recommended phase II dose (RP2D) of vistusertib in patients with GBM receiving TMZ at first progression following primary treatment. Vistusertib was administered at a starting dose of 100 mg bid 2 days on/5 days off weekly with TMZ 150 mg/m2 daily for 5 days/28-days cycle. Dose escalation was according to a 3 + 3 design. Secondary objectives included assessment of vistusertib safety and toxicity profile, and preliminary efficacy. 15 patients were enrolled in the study (median age 66 (range 51-77), females 8). Vistusertib 125 mg BID in combination with TMZ 150 mg/m2 daily for 5 days was well tolerated. Vistusertib treatment-related adverse events were generally grade 1-2, with the most frequently reported being fatigue, gastrointestinal symptoms, and rash. Of 13 response evaluable patients, 1 patient (8%) had a partial response ongoing at 7.6 months of follow-up, and 5 patients had stable disease (38%) as best response (median duration 9.6 months, range 3.7-not yet reached). Six-month progression-free survival (PFS) rate was 26.6%. Combination of vistusertib with TMZ in GBM patients at first recurrence demonstrated a favorable safety profile at the tested dose levels.
Keywords: AZD2014; Clinical trial; Glioblastoma; Temozolomide; mTOR inhibitor; mTORC2.