A Phase I Trial of LY2510924, a CXCR4 Peptide Antagonist, in Patients with Advanced Cancer

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 3þ3 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 þ hematopoietic 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 treatmentemergent 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 þ cell counts in peripheral blood up to 18-fold. Conclusions: LY2510924 demonstrated CD34 þ cell mobilization at doses !2.5 mg/day with a tolerable safety profile up to an MTD of 20 mg/day. Clin Cancer Res; 20(13);

Identification of LY2510924, a Novel Cyclic Peptide CXCR4 Antagonist That Exhibits Antitumor Activities in Solid Tumor and Breast Cancer Metastatic Models

“…LY2510924 is a small cyclic peptide containing a number of non-natural amino acids with improved in vivo stability. In a completed phase I study of patients with advanced cancer, the in vivo half-life of LY2510924 at 20 mg, the recommended phase II dose was 9.16 hours, and the pharmacodynamic effect based on stem cell mobilization was robust (20). Because of its high potency and in vivo stability, LY2510924 was suitable for once daily injection for chronic treatment in a clinical setting.…”

“…The in vivo half-life and other PK properties support further investigation of LY2510924 in the clinic. Indeed, in a completed phase I clinic study, LY2510924 has a half-life of 9.16 hours in the confirmed phase II dose (20).…”

“…LY2510924 is a small cyclic peptide containing non-natural amino acids with a molecular weight of 1,189.74 Dalton. LY2510924 has a dramatically improved in vivo stability with a half-life of 3 to 5 hours in preclinical species and 9.16 hours in humans at the recommended phase II dose (20). It is a potent inhibitor of the SDF-1 and CXCR4 interaction and the downstream signaling and functions.…”

New agents in HSC mobilization

“…Unlike POL6326, the small molecule CXCR4 inhibitor TG-0054 (Burixafor) [29] and the cyclic peptide BKT-140 [30] have been tested with G-CSF and shown to synergistically augment HSC mobilization when given as a single dose after a standard course of G-CSF, results which were corroborated in human volunteers and patients with haematological malignancies [31][32][33][34]. Other promising CXCR4 antagonists in development for HSC mobilization include the cyclic peptide LY2510924 [35][36][37] and the small molecule ALT-1188 [38]. Notably, ALT-1188 has been shown to effectively mobilize murine HSPC when given as a single dose and synergistically when used in combination with G-CSF [38].…”

A novel CXCR4 antagonist IgG1 antibody (PF-06747143) for the treatment of hematologic malignancies

“…It is important to note that the ability of anti-CXCR4 agents to simply mobilize cells appears to be insufficient to drive antitumor activity. For instance, the CXCR4 peptide antagonists LY2510924 24 and BKT140/BL8040/TN14003 25 induce cell mobilization as monotherapies but failed to reduce tumor burden in clinical trials. 25,26 Interestingly, the CXCR4 partial agonist small molecule AMD3100 (Plerixafor; Mozobil), which induces mobilization of leukemic blasts from the BM, is undergoing clinical evaluation in hematologic malignancies in combination with chemotherapy, as a means to eliminate the mobilized cancer cells.…”