Phase II trial of the epothilone analog sagopilone (ZK219477; ZK EPO) in patients with recurrent glioblastoma: Initial report of the EORTC study 26061

Abstract

2015 Background: Sagopilone is a fully synthetic analog of epothilone B. It inhibits microtubule depolarization and induces cell cycle arrest. Not a substrate for ABCB1, good penetration into normal brain is expected. In orthotopically implanted brain tumor models it has demonstrated antitumor activity. This early clinical trial aims at evaluating the efficacy of sagopilone in recurrent glioblastoma, the success rate as a composite of response or progression-free survival at 6 months [PFS-6] is the primary endpoint. Methods: Pts with measurable first recurrence or progressive disease after ≥ 3 mo from the end of radiochemotherapy were eligible, if WHO performance status [PS] ≤ 2, no significant co-morbidity and adequate hematological, liver and renal function tests. Sagopilone (16mg/m²) was administered as 3 h infusion every 3 wks. Response was assessed every 2 cycles (6 wks). Fleming's one stage design was selected assuming: P0, unacceptable success rate=8%; P1, target success rate=23%; if ≥ 5 successes were observed in 35 evaluable pts, the drug would be considered interesting in this indication. Results: Between 12/2006 and 08/2007, 38 (36 eligible treated) pts from 7 institutions were enrolled: median age 57 yrs (range 20–76), PS was 0 in 14 pts, PS 1 in 17 pts and PS 2 in 6 pts. A total of 100 cycles were administered (median 2, range 1–6), main reason for treatment discontinuation was disease progression in 82%. Related toxicity (grade 3) was: leucopenia (2 pts), neutropenia (3 pts), fatigue (2 pts), neuropathy (1 pt). Grade 1 and grade 2 neuro-sensory toxicity was also reported in 35% and 5% of pts, respectively. No objective response was documented, 13 pts had disease stabilization as best response. Two pts achieved PFS-6, in 2 pts follow-up is too early. The current success rate is 5.7%, (95%CI 0.007–19.0), the actuarial PFS-6 is 9.4% (95% CI 2.5–22.0). Conclusions: The envisaged activity mark can not be reached. Hematotoxicity and neurosensory alterations are the main toxicities. Our results do not support further exploration of sagopilone at this dose and schedule in malignant glioma. This trial has been supported in part by an unrestricted grant of Bayer-Schering Pharma, Berlin, Germany. No significant financial relationships to disclose.