title: A Randomized, Open-Label Phase 2 Study of the CXCR4 Inhibitor LY2510924 in Combination with Sunitinib Versus Sunitinib Alone in Patients with Metastatic Renal Cell Carcinoma (RCC).
abstract: The chemokine (C-X-C Motif) receptor 4 (CXCR4) and its ligand, stromal-cell derived factor-1 (SDF-1), are frequently overexpressed in a variety of solid tumors, and are believed to play important roles in the regulation of organ-specific metastasis, tumor growth, invasion, and survival. In this randomized Phase 2 trial, we evaluated the safety and efficacy of LY2510924 (LY), a peptide antagonist of CXCR4, combined with sunitinib (SUN) in the first-line treatment of advanced renal cell carcinoma (RCC).
  
  
  
  Eligible patients were randomized (2:1) to receive LY (20 mg SC daily) + SUN (50 mg PO daily for 4 weeks followed by 2 weeks off) or SUN alone. Response was assessed after two cycles; patients continued treatment until tumor progression or intolerable toxicity. The study was powered to detect a 47 % increase in median progression-free survival (PFS).
  
  
  
  One hundred eight patients were randomized and treated (LY + SUN, 72; SUN, 36); median duration of treatment of five cycles. Observed median PFS was 8.1 months with LY + SUN and 12.3 months with SUN; Bayesian time-to-event HR 1.23; 95 % credible interval: 0.74, 1.96. LY was well tolerated; the toxicity profile was typical of SUN. No efficacy differences were seen between treatments groups when subsets with high versus low levels of CXCR4 tumor expression were compared.
  
  
  
  The addition of LY to SUN in the first-line treatment of metastatic RCC was well tolerated, but did not improve the PFS or overall survival (OS) vs. SUN alone. CXCR4 remains an unproven therapeutic target for the treatment of RCC.
  
  
  
  
  
  
  
  NCT01391130.
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 250 25th Ave N #100, Nashville, TN, 37203, USA. John.Hainsworth@scresearch.net.
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
authors.affiliation: Florida Cancer Specialists, Fort Myers, FL, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Reeves
authors.affiliation: Florida Cancer Specialists, St. Petersburg, FL, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mace
authors.affiliation: Oncology Hematology Care, Cincinnati, OH, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Crane
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Oday
authors.initials: O
authors.lastname: Hamid
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Stille
authors.affiliation: PharPoint Research Inc, Durham, NC, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Flynt
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Roberson
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: John
authors.initials: J
authors.lastname: Polzer
authors.affiliation: Tennessee Oncology, Chattanooga, TN, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Arrowsmith
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009362:Neoplasm Metastasis; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; C527276:CXCR4 protein, human; D007211:Indoles; C000595455:LY2510924; D010456:Peptides, Cyclic; D011758:Pyrroles; D019718:Receptors, CXCR4; D000077210:Sunitinib