title: A phase I trial of LY2510924, a CXCR4 peptide antagonist, in patients with advanced cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 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.
authors.affiliation: Authors' Affiliations: US Oncology Research/Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada; matthew.galsky@mssm.edu.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
authors.affiliation: Authors' Affiliations: US Oncology Research/Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada;
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.affiliation: US Oncology Research/Virginia Oncology Associates, Norfolk, Virginia;
authors.forename: Paul
authors.initials: P
authors.lastname: Conkling
authors.affiliation: The Chorus Group, Eli Lilly and Company;
authors.forename: Eyas
authors.initials: E
authors.lastname: Raddad
authors.affiliation: The Chorus Group, Eli Lilly and Company;
authors.forename: John
authors.initials: J
authors.lastname: Polzer
authors.affiliation: The Chorus Group, Eli Lilly and Company;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Roberson
authors.affiliation: The Chorus Group, Eli Lilly and Company;
authors.forename: John R
authors.initials: JR
authors.lastname: Stille
authors.affiliation: Georgia Cancer Specialists, PC, Atlanta, Georgia.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Saleh
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana; and.
authors.forename: Donald
authors.initials: D
authors.lastname: Thornton
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology*; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C000595455:LY2510924; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4