title: Phase I dose-escalation study of intravenous aflibercept in combination with docetaxel in patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase I study cohort investigated aflibercept in combination with docetaxel in patients with advanced solid tumors.
  
  
  METHODS
  Eligible patients had metastatic or nonresectable cancer for which docetaxel was considered appropriate. Patients received intravenous aflibercept (either 2, 4, 5, 6, 7, or 9 mg/kg) with docetaxel (75 mg/m(2)) on day 1 every 3 weeks until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLT) during cycle 1 and to determine the aflibercept recommended phase II trial dose (RP2D) for combination with docetaxel. Pharmacokinetics, tolerability, and antitumor activity were also investigated.
  
  
  RESULTS
  Fifty-four patients (mean age, 56 y) were enrolled. Most had prior chemotherapy (96%) and most (24.1%) had breast cancer. In the dose-escalation phase (n = 34), there were three DLTs: grade 4 neutropenic infection (2 mg/kg), grade 3 dysphonia (7 mg/kg), and grade 2 hypertension (9 mg/kg). An excess of free-over-bound aflibercept was observed at doses of 5 mg/kg or more. The pharmacokinetics of aflibercept and docetaxel were not modified by coadministration. Aflibercept (6 mg/kg) was defined as the RP2D based on DLT and pharmacokinetic data. Overall, the most frequent grade 3/4 adverse events (AE) were neutropenia (85.2%), leukopenia (74.1%), hypertension (18.5%), and stomatitis (16.7%). AEs associated with vascular endothelial growth factor blockade included epistaxis (all grades, 83.3%), proteinuria (68.5%), dysphonia (68.5%), and hypertension (53.7%). Seven patients had partial responses, and 32 patients had stable disease (>3 months in 18 patients).
  
  
  CONCLUSIONS
  On the basis of findings from this study, aflibercept (6 mg/kg) was the dose recommended for further clinical development.
authors.affiliation: Centre Georges François Leclerc, France. nisambert@cgfl.fr
authors.forename: Nicolas
authors.initials: N
authors.lastname: Isambert
authors.forename: Gilles
authors.initials: G
authors.lastname: Freyer
authors.forename: Sylvie
authors.initials: S
authors.lastname: Zanetta
authors.forename: Benoît
authors.initials: B
authors.lastname: You
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.forename: Claire
authors.initials: C
authors.lastname: Falandry
authors.forename: Laure
authors.initials: L
authors.lastname: Favier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Assadourian
authors.forename: Karen
authors.initials: K
authors.lastname: Soussan-Lazard
authors.forename: Samira
authors.initials: S
authors.lastname: Ziti-Ljajic
authors.forename: Veronique
authors.initials: V
authors.lastname: Trillet-Lenoir
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000906:Antibodies; D011993:Recombinant Fusion Proteins; D043823:Taxoids; C533178:aflibercept; D000077143:Docetaxel; D040262:Receptors, Vascular Endothelial Growth Factor