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

Mené sur 45 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la dose maximale tolérée et divers paramètres pharmacocinétiques d'un composé appelé LY2510924, un antagoniste peptidique bloquant la liaison entre SDF-1 et CXCR4

Résumé en anglais

Purpose: Over-expression 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 (SDF-1) 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+ 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 maximally 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 9 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.