Study design and participants

This was a phase I, two-stage, multicentre, open-label, dose-escalation study conducted in adult patients (age ≥18 years) with newly diagnosed glioblastoma. Patients with primary glioblastoma or patients whose previously existing lower-grade glioma underwent transformation were eligible.

Stage I of the study included patients who completed concomitant TMZ-radiotherapy prior to study entry to estimate the MTD of buparlisib combined with TMZ in adjuvant treatment of glioblastoma. Buparlisib dose escalation was evaluated sequentially in adjuvant cycle 1 (A1) and in adjuvant cycle 2 (A2). Stage II included patients who had received only surgery prior to study entry to estimate the MTD/RP2D of buparlisib in the concomitant phase (TMZ-radiotherapy; C), A1, A2 and beyond (cycle 3 +) (figure 1).

Study design. BKM120, buparlisib; GBM, glioblastoma multiforme; MTD, maximum tolerated dose; q, every; RP2D, recommended phase II dose; RT, radiotherapy.

Patients enrolled into stage I must have received at least 75% of planned radiotherapy (60 Gy) with TMZ treatment during the concomitant phase; had an absolute neutrophil count ≥1.5 × 10⁹/L, platelet count ≥100 × 10⁹/L and no occurrence of common toxicity criteria grade ≥2 non-haematological toxicity (except for alopecia, nausea and vomiting) during the concomitant phase; and completed TMZ therapy in the concomitant phase 4 to 6 weeks prior to enrolment. Patients enrolled into stage II were required to have completed primary glioblastoma resection 2to 6 weeks prior to enrolment. Patients must have recovered from the definitive surgical procedure for glioblastoma.

In stage I, a minimum of six evaluable patients must have completed the combination treatment in adjuvant phase A1 and A2 sequentially, with a minimum of 60 mg/day buparlisib demonstrated as tolerable in treatment phase A1, before the initiation of stage II. In stage II, a minimum of nine evaluable patients (including those in the earlier dose-escalation cohorts) must have completed the combination treatment in the concomitant phase (C), adjuvant phase cycle 1 (A1) and adjuvant phase cycle 2 (A2) sequentially, demonstrating the tolerability of the dose sequence, in order to confirm the RP2D and/or MTD, which was to be declared when a minimum of three evaluable patients completed the dose sequence and shown it was tolerable.

The concomitant phase was of 42 days duration during which the patients received buparlisib in combination with TMZ (75 mg/m²/day) and radiotherapy (60 Gy in 30 fractions), followed by a rest phase of 4 to 6 weeks duration. In the adjuvant phase, patients received buparlisib in combination with TMZ for 12 cycles or until disease progression or death, withdrawal of consent and start of another antineoplastic treatment whichever occurred first.

This study was conducted in accordance with the Good Clinical Practice guidelines and the Declaration of Helsinki. Written informed consent was obtained from all the patients.