Safety, Pharmacokinetics, and Activity of GRN1005, a Novel Conjugate of Angiopep-2, a Peptide Facilitating Brain Penetration, and Paclitaxel, in Patients with Advanced Solid Tumors

GRN1005 is a novel peptide–drug conjugate composed of paclitaxel covalently linked to a peptide, angiopep-2, that targets the low-density lipoprotein receptor-related protein 1. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and efficacy of GRN1005 in patients with advanced solid tumors. Patients in sequential cohorts (one patient per cohort until grade 2 toxicity, then 3 þ3 design) received intravenous GRN1005 at escalating doses between 30 and 700 mg/m 2 once in every 21 days. In the maximum tolerated dose (MTD) expansion group, patients were required to have brain metastases. Fifty-six patients received GRN1005, including 41 with brain metastases (median number of prior therapies ¼ 4). MTD was 650 mg/m 2 ; the main dose-limiting toxicity was myelosuppression. Sixteen of 20 patients dosed at the MTD had brain metastases. Pharmacokinetics was dose linear and the mean terminal-phase elimination half-life was 3.6 hours. No evidence of accumulation was observed after repeat dosing. No anti-GRN1005 antibodies were detected.Fiveofthe20patients(25%)dosedat650mg/m 2 (MTD),threeofwhomhadprevioustaxanetherapy, achievedanoverallpartialresponse(breast,n ¼2;non–smallcelllungcancer,n ¼2;andovariancancer,n ¼1); responsesinallfivepatientswerealsoaccompaniedbyshrinkageofbrainlesions(�17%to �50%).Inaddition, sixpatients(11%;doses30–700mg/m 2 )experiencedstablediseasethatlasted4monthsormore.GRN1005was well tolerated and showed activity in heavily pretreated patients with advanced solid tumors, including those who had brain metastases and/or failed prior taxane therapy. Mol Cancer Ther; 11(2); 308–16. � 2011 AACR.