Results of a phase I trial to assess the safety of macitentan in combination with temozolomide for the treatment of recurrent glioblastoma

Abstract

Background: There is an urgent need for additional therapies to treat recurrent glioblastoma (GBM). Preclinical studies suggest that high dose macitentan, an oral dual endothelin receptor antagonist, enhances the cytotoxic effects of temozolomide (TMZ) in GBM, improving survival. This phase I trial investigated the maximum tolerated dose of macitentan combined with TMZ in patients with recurrent GBM and assessed the safety and tolerability of high dose macitentan in these patients (NCT01499251).

Methods: Adults with recurrent GBM received ascending doses of macitentan from 30 mg once daily concomitantly with TMZ. Safety and tolerability were assessed in addition to exploratory efficacy and pharmacokinetic endpoints. An ancillary study examined biomarker expression following macitentan treatment prior to surgical resection of recurrent GBM.

Results: Thirty-eight patients with recurrent GBM were administered macitentan doses up to 300 mg once daily; no dose-limiting toxicities were observed, and a maximum tolerated dose was not determined. All patients experienced at least one treatment-emergent adverse event (TEAE), the majority associated with GBM or TMZ treatment. TEAEs related to macitentan and TMZ were reported for 16 (42.1%) and 26 (68.4%) patients, respectively, with no serious macitentan-related TEAEs. Macitentan concentrations increased with dose, with no plateau in exposure. Substantial heterogeneity was observed in the expression of efficacy biomarkers within tumors. The Kaplan-Meier estimate of median overall survival across all dose groups was 9.4 (95% CI 8.5, 13.4) months.

Conclusion: High-dose macitentan was well tolerated in recurrent GBM patients concomitantly receiving TMZ. TEAEs were consistent with those seen in patients receiving either drug individually.

Keywords: glioblastoma; macitentan; phase I; recurrent; temozolomide.

© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.

Figures

Figure 1.

Study design. The phase I dose escalation period followed a conventional 3+3 dose escalation design (Supplementary methods). A 30-day follow-up period following discontinuation of the study treatment was included for assessment of adverse events/serious adverse events, vital signs, physical examination and concomitant medications. Dose adjustments of TMZ were permitted if required. *End of treatment occurred if study treatment was discontinued due to disease progression, death or for another reason. **Assessment of an additional dose was planned but not completed due to early termination. †Macitentan was stopped 1-day prior to surgery and restarted 3–5 weeks post-surgery. DLT: Dose-limiting toxicity.

Figure 2.

Patient disposition. The phase Ib study included 9 patients receiving 150 mg macitentan who were in the phase I dose escalation study and 6 additional patients that were not included in the phase I dose escalation study. Thirty-six patients discontinued study treatment before completing 12 cycles of treatment; 89.5% of early discontinuations were due to progressive disease. †1 patient in the 120 mg group and 3 patients in the 150 mg group were replaced due to incorrect treatment (Supplementary methods). Patients were contacted every 3 months until the end of the study to assess vital status.

Figure 3.

Macitentan and ACT-132577 plasma concentrations over 24 hours at steady state in the recurrent GBM patient population. (a) 24-hour PK profile for plasma macitentan concentrations after 150 mg macitentan at Day 14. N = 6 at each timepoint except N = 5 at 24 h. (b) 24-hour PK profile for plasma ACT-132577 concentrations after 150 mg macitentan at Day 14. N = 6 at each timepoint, except N = 5 at 24h. Data at each timepoint are mean ± SD.