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.

Abstract

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 + 3 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 = 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. Five of the 20 patients (25%) dosed at 650 mg/m(2) (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/m(2)) experienced stable disease that lasted 4 months or more. 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.

• Authors: Razelle Kurzrock, Nash Gabrail, Chandtip Chandhasin, Stacy Moulder, Carrie Smith, Andrew Brenner, Kamalesh Sankhala, Alain Mita, Kelly Elian, Danielle Bouchard, John Sarantopoulos
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 2 Pg. 308-16 (Feb 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22203732 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Peptides
• paclitaxel-Angiopep-2 conjugate
• Paclitaxel

Topics

• Adult
• Aged
• Aged, 80 and over
• Alopecia (chemically induced)
• Antineoplastic Agents, Phytogenic (adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• Brain (metabolism)
• Cohort Studies
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Fatigue (chemically induced)
• Female
• Humans
• Infusions, Intravenous
• Male
• Metabolic Clearance Rate
• Middle Aged
• Neoplasms (drug therapy, metabolism, pathology)
• Neutropenia (chemically induced)
• Paclitaxel (adverse effects, pharmacokinetics, therapeutic use)
• Peptides
• Treatment Outcome
• Young Adult