Phase I study of GRN1005 in recurrent malignant glioma
Mené sur 63 patients atteints d'un gliome récidivant, cet essai de phase I évalue un conjugué peptide-médicament conçu pour traverser la barrière hémato-encéphalique, le GRN1005
Purpose: GRN1005 is a peptide-drug conjugate with the ability to penetrate the blood-brain barrier (BBB) and tumor cells by targeting the low-density lipoprotein receptor-related protein-1 (LRP-1). We conducted a first-in-human phase I trial of GRN1005 in patients with recurrent glioma. Methods: Patients received GRN1005 by intravenous infusion every three weeks. Doses were escalated using a modified Fibonacci scheme. Study objectives included safety, tolerability, identification of the maximum tolerated dose (MTD), pharmacokinetics, and preliminary evidence of efficacy. Tumor extracted from patients undergoing surgery following administration of GRN1005 was analyzed to determine if therapeutic concentrations of GRN1005 were achieved. Results: 63 patients received GRN1005 at doses of 30-700 mg/m2 every 3 weeks. Therapy was well-tolerated with neutropenia, leucopenia and fatigue as the most frequent drug-associated grade 3/4 or higher toxicities. The MTD was 650 mg/m2 every 3 weeks. Dose-limiting toxicities (DLTs) were grade 3 mucositis and grade 4 neutropenia. There was no evidence of CNS toxicity or antibody production. Pharmacokinetic analysis showed exposure to GRN1005 was dose proportional. We observed one complete and two partial responses. 8/27 patients dosed ≥ 420 mg/m2 had stable disease which lasted a median of 51 days. Therapeutic concentrations of GRN1005 and free paclitaxel were demonstrated in tumor tissue of surgical patients dosed with ≥ 200 mg/m2. Conclusion: GRN1005 delivers paclitaxel across the BBB and achieves therapeutic concentrations in tumor tissue. It has similar toxicity to paclitaxel and appears to have activity in recurrent glioma. The recommended phase II dose is 650 mg/m2 every 3 weeks.