RT Journal Article
SR Electronic
T1 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
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP molcanther.0566.2011
DO 10.1158/1535-7163.MCT-11-0566
A1 Kurzrock, Razelle
A1 Gabrail, Nashat Y.
A1 Chandhasin, Chandtip
A1 Moulder, Stacy L.
A1 Smith, Carrie
A1 Brenner, Andrew J
A1 Sankhala, Kamalesh
A1 Mita, Alain C.
A1 Elian, Kelly
A1 Bouchard, Danielle C
A1 Sarantopoulos, John
YR 2011
UL http://mct.aacrjournals.org/content/early/2011/12/22/1535-7163.MCT-11-0566.abstract
AB GRN1005 is a novel peptide-drug conjugate (PDC) comprised of paclitaxel covalently linked to a peptide, Angiopep-2, that targets the low-density lipoprotein receptor-related protein 1 (LRP-1). This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK) and efficacy of GRN1005 in patients with advanced solid tumors. Patients in sequential cohorts (one patient per cohort until Grade 2 toxicity, then 3 + 3 design) received intravenous GRN1005 at escalating doses between 30 mg/m2 and 700 mg/m2 once 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 = 4). MTD was 650 mg/m2; the main dose-limiting toxicity was myelosuppression. Sixteen of 20 patients dosed at the MTD had brain metastases. PK 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. Five of the 20 patients (25%) dosed at 650 mg/m2 (MTD), three of whom had previous taxane therapy, achieved an overall partial response (breast, n=2; non-small cell lung cancer, n=2; and ovarian cancer, n=1); responses in all five patients were also accompanied by shrinkage of brain lesions (-17% to -50%). In addition, six patients (11%; doses 30-700 mg/m2) experienced stable disease that lasted > 4 months. GRN1005 was 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.