Abstract 1419: A phase I study of the CXCR4 peptide antagonist LY2510924 in patients with advanced cancer.
Authors: Vogelzang Nicholas , Saleh Mansoor , Conkling Paul , Abu-Raddad Eyas J. , Polzer John P. , Roberson Stephanie , Stille John R. , Thornton Donald E. 
Published: August 2014

Abstract
Background: The over-expression of C-X-C motif receptor 4 (CXCR4), a chemokine receptor implicated in tumor progression, tumor cell growth, migration, and invasion, correlates with a worse prognosis. LY2510924 is a selective peptide antagonist to CXCR4. This peptide blocks stromal cell-derived factor-1 (SDF-1), the only known ligand to CXCR4, from binding to the receptor. Disruption of the CXCR4/SDF-1 axis with CXCR4 antagonists is known to mobilize WBC, neutrophils, and CD34+ cells. The primary objective of this study was to determine the maximum tolerated dose (MTD). Secondary objectives were to determine safety, pharmacokinetics, efficacy, and pharmacodynamic response, which included mobilization of CD34+ hematopoietic stem cells into the peripheral blood.
Material & Methods: This phase I study in patients (pts) with advanced cancer included two Parts: a 3+3 dose escalation (Part A) and dose confirmation (Part B). LY2510924 was administered as a daily injection subcutaneously (s.c.) on a 28-day cycle.
Results: Forty-five pts, 98% with solid tumors, were enrolled onto study, 25 in Part A and 20 in Part B. The median age was 67.0 years (range: 39-86), 51.1% were male, and 80.0% were Caucasian. The Eastern Cooperative Oncology Group performance status was 1 for 73.3% of pts. In Part A, pts in 6 cohorts were treated with doses of LY2510924: 1.0 (n=3), 2.5 (n=5), 5.0 (n=3), 10 (n=3), 20 (n=4), and 30 mg/day (n=7). Two pts in the 30 mg/day cohort experienced dose-limiting toxicities, grade 3 neutrophil count increase. The MTD was determined to be 20 mg/day. Pts in Part B were treated with either 2.5 (n=10) or 20 mg/day (n=10). For Parts A and B combined, the most frequently reported (≥15%) treatment emergent adverse events (TEAE), regardless of causality, included fatigue, nausea, constipation, anemia, and anorexia. The most common grade 3 TEAE were increased neutrophil count, anemia, asthenia, and dypsnea (all occurring in 4.4% of pts). There were no grade 4 TEAE. The best response was stable disease for 9 pts (20.0%). At the end of Cycle 1, mean peak LY2510924 plasma concentration (Cmax) and the 24-hour area under the plasma concentration vs. time curve (AUC) increased slightly more than dose proportionally. Mean Cmax and AUC ranged from 18.8 ng/mL to 1250 ng/mL, and 61.5 ng•h/mL to 5720 ng•h/mL, respectively, in the 1-30 mg dose range. Median time to Cmax was 0.5 hours independent of dose. Receptor occupancy was consistently high with median values of 96.9-100% for 2.5 mg, 20 mg and 30 mg, between 0.5 hours through 24 hours after dosing. There was an up to 18-fold mean increase from baseline in CD34+ cell count in peripheral blood, with an apparent dose-response relationship between 1mg and 10 mg, and little additional response with 20 mg or 30 mg. The increase persisted to the end of Cycle 1, but was somewhat blunted.
Conclusions: LY2510924 demonstrated CD34+ cell mobilization with an acceptable safety profile up to an MTD of 20 mg/day (s.c.).
Citation Format: Nicholas Vogelzang, Mansoor Saleh, Paul Conkling, Eyas J. Abu-Raddad, John P. Polzer, Stephanie Roberson, John R. Stille, Donald E. Thornton. A phase I study of the CXCR4 peptide antagonist LY2510924 in patients with advanced cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1419. doi:10.1158/1538-7445.AM2013-1419