title: Phase 1 study of the anti-vascular endothelial growth factor receptor 3 monoclonal antibody LY3022856/IMC-3C5 in patients with advanced and refractory solid tumors and advanced colorectal cancer.
abstract: OBJECTIVE
  Metastasis of solid tumors to regional lymph nodes is facilitated by tumor lymphangiogenesis, which is primarily mediated by the vascular endothelial growth factor receptor 3 (VEGFR-3). We conducted a phase 1 dose-escalation (part A) study of the VEGFR-3 human immunoglobulin G subclass 1 monoclonal antibody LY3022856 in advanced solid tumors, followed by a colorectal cancer (CRC) expansion (part B).
  
  
  METHODS
  Part A evaluated the safety profile and maximum tolerated dose (MTD) of LY3022856 in patients treated intravenously at doses of 5-30 mg/kg weekly (qwk). Part B further evaluated tolerability in CRC patients treated with 30 mg/kg. Secondary objectives were pharmacokinetics, anti-tumor activity, and pharmacodynamics (exploratory).
  
  
  RESULTS
  A total of 44 patients (23 in part A; 21 in part B) were treated; only one dose-limiting toxicity was observed at the lowest dose level. The MTD was not reached. Treatment-emergent adverse events (TEAEs) of any grade included in ≥15 % of all patients were: nausea (41 %), fatigue (32 %), vomiting (30 %), decreased appetite (27 %), pyrexia (25 %), peripheral edema (23 %), and urinary tract infection (UTI, 20 %). The most common grade 3/4 TEAEs included UTI and small intestinal obstruction (7 % each). No radiographic responses were noted. Median progression-free survival in part B was 6.3 weeks (95 % confidence interval: 5.1, 14.4), and a best overall response of stable disease was observed in 4 CRC patients (19.0 %).
  
  
  CONCLUSIONS
  LY3022856 was well tolerated up to a dose of 30 mg/kg qwk, but with minimal anti-tumor activity in CRC. CLINICALTRIALS.
  NCT01288989.
authors: Tufts Cancer Center - Medical Center, Tufts University School of Medicine, 800 Washington St., Ste. 7099, 7-South, Boston, MA, 02111, USA. wsaif@tuftsmedicalcenter.org.
authors: Muhammad Wasif
authors: MW
authors: Saif
authors: Illinois CancerCare, Peoria, IL, USA.
authors: James A
authors: JA
authors: Knost
authors: University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors: E Gabriela
authors: EG
authors: Chiorean
authors: Eli Lilly and Company, Bridgewater, NJ, USA.
authors: Siva Rama Prasad
authors: SR
authors: Kambhampati
authors: Eli Lilly and Company, Indianapolis, IN, USA.
authors: Danni
authors: D
authors: Yu
authors: Eli Lilly and Company, New York, NY, USA.
authors: Bronislaw
authors: B
authors: Pytowski
authors: Eli Lilly and Company, Bridgewater, NJ, USA.
authors: Amy
authors: A
authors: Qin
authors: Eli Lilly and Company, Bridgewater, NJ, USA.
authors: John S
authors: JS
authors: Kauh
authors: Indiana University, Indianapolis, IN, USA.
authors: Bert H
authors: BH
authors: O'Neil
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C000619939:LY3022856; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: Colorectal cancer; Lymphangiogenesis; Monoclonal antibody; Vascular endothelial growth factor (VEGF)