A phase I trial of LY2510924, a CXCR4 peptide antagonist, in patients with advanced cancer

Matthew D. Galsky, Nicholas J. Vogelzang, Paul Conkling, John Polzer, Stephanie Roberson, John R. Stille, Mansoor Saleh, Donald Thornton

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)

Abstract

Purpose: Overexpression of C-X-C motif receptor 4 (CXCR4) is implicated in tumor progression. LY2510924 is a peptide antagonist, which blocks stromal cell-derived factor-1 (SDF1) from CXCR4 binding. Experimental Design: This phase I study included two parts: a 3+3 dose escalation (part A) and dose confirmation (part B). LY2510924 was administered as a daily subcutaneous injection on a 28-day cycle. The primary objective was to determine the recommended phase II dose. Secondary objectives included safety, pharmacokinetics, efficacy, and pharmacodynamic response, including mobilization of CD34+ hemato-poietic stem cells into the peripheral blood. Results: Forty-five patients were enrolled, 25 in part A and 20 in part B. Patients were administered increasing doses of LY2510924: 1.0, 2.5, 5.0, 10,20, and 30 mg/day for part A and 2.5 or 20 mg/day for part B. Two patients (30-mg/day cohort) experienced dose-limiting toxicities of grade 3 increased neutrophil count. The maximum tolerated dose (MTD) was 20 mg/day. The most common drug-related treatment-emergent adverse events were fatigue (9%), injection-site reaction (9%), injection site pruritus (7%), and nausea (7%). The best response was stable disease for nine patients (20%). At the end of cycle 1, mean peak LY2510924 plasma concentration and the 24-hour area under the plasma concentration versus time curve increased slightly more than dose proportionally. LY2510924 dose dependently increased CD34+ cell counts in peripheral blood up to 18-fold. Conclusions: LY2510924 demonstrated CD34+ cell mobilization at doses ≥2.5 mg/day with a tolerable safety profile up to an MTD of 20 mg/day.

Original languageEnglish
Pages (from-to)3581-3588
Number of pages8
JournalClinical Cancer Research
Volume20
Issue number13
DOIs
Publication statusPublished - 1 Jul 2014
Externally publishedYes

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