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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. We conducted a first-in-human phase I trial of GRN1005 in patients with recurrent glioma. METHODS: Patients received GRN1005 by intravenous infusion every 3 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 whether therapeutic concentrations of GRN1005 were achieved. RESULTS: Sixty-three patients received GRN1005 at doses of 30 to 700 mg/m(2) 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/m(2) every 3 weeks. Dose-limiting toxicities were grade 3 mucositis and grade 4 neutropenia. There was no evidence of central nervous system toxicity or antibody production. Pharmacokinetic analysis showed that exposure to GRN1005 was dose proportional. We observed one complete and two partial responses. Eight of 27 patients dosed ≥ 420 mg/m(2) had stable disease, which lasted a median of 51 days. Therapeutic concentrations of GRN1005 and free paclitaxel were shown in tumor tissue of surgical patients dosed with ≥ 200 mg/m(2). 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/m(2) every 3 weeks.
Drappatz et al. (Fri,) studied this question.