title: Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: a randomized, placebo-controlled phase II AIO trial with serum biomarker program.
abstract: As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response.
  
  
  
  This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively.
  
  
  
  Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70-1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50-1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed.
  
  
  
  Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted.
  
  
  
  This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009.
authors: University Medical Center, Johannes Gutenberg-University Mainz, I. Medizinische Klinik und Poliklinik, Langenbeckstraße 1, 55131, Mainz, Germany. markus.moehler@unimedizin-mainz.de.
authors: Markus
authors: M
authors: Moehler
authors: University Medical Center, Johannes Gutenberg-University Mainz, I. Medizinische Klinik und Poliklinik, Langenbeckstraße 1, 55131, Mainz, Germany.
authors: Irina
authors: I
authors: Gepfner-Tuma
authors: University Medical Center, Johannes Gutenberg-University Mainz, I. Medizinische Klinik und Poliklinik, Langenbeckstraße 1, 55131, Mainz, Germany.
authors: Annett
authors: A
authors: Maderer
authors: Charité Campus Virchow-Klinikum, Berlin, Germany.
authors: Peter C
authors: PC
authors: Thuss-Patience
authors: University Hospital Halle (Saale), Halle (Saale), Germany.
authors: Joern
authors: J
authors: Ruessel
authors: Hämatologisch-Onkologische Praxis Eppendorf, Hamburg, Germany.
authors: Susanna
authors: S
authors: Hegewisch-Becker
authors: Kliniken Essen-Mitte - Evang. Huyssens-Stiftung, Essen, Germany.
authors: Hansjochen
authors: H
authors: Wilke
authors: Krankenhaus Nordwest, Frankfurt, Germany.
authors: Salah-Eddin
authors: SE
authors: Al-Batran
authors: Krankenhaus Nordwest, Frankfurt, Germany.
authors: Mohammad-Reza
authors: MR
authors: Rafiyan
authors: Evangelisches Krankenhaus Bielefeld, Bielefeld, Germany.
authors: Florian
authors: F
authors: Weißinger
authors: University Hospital Halle (Saale), Halle (Saale), Germany.
authors: Hans-Joachim
authors: HJ
authors: Schmoll
authors: Kliniken Nordoberpfalz - Klinikum Weiden, Weiden, Germany.
authors: Frank
authors: F
authors: Kullmann
authors: Gesundheitszentrum St. Marien GmbH, Amberg, Germany.
authors: Ludwig Fischer
authors: LF
authors: von Weikersthal
authors: Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
authors: Jens T
authors: JT
authors: Siveke
authors: University Medical Center, Johannes Gutenberg-University Mainz, I. Medizinische Klinik und Poliklinik, Langenbeckstraße 1, 55131, Mainz, Germany.
authors: Jens
authors: J
authors: Weusmann
authors: Leopoldina Krankenhaus, Schweinfurt, Germany.
authors: Stephan
authors: S
authors: Kanzler
authors: Marienkrankenhaus Darmstadt, Darmstadt, Germany.
authors: Carl Christoph
authors: CC
authors: Schimanski
authors: Praxisgemeinschaft für Onkologie und Urologie, Wilhelmshaven, Germany.
authors: Melanie
authors: M
authors: Otte
authors: Interdisciplinary Center for Clinical Trials (IZKS), Mainz, Germany.
authors: Lukas
authors: L
authors: Schollenberger
authors: Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) of the University Medical Center Mainz, Mainz, Germany.
authors: Jochem
authors: J
authors: Koenig
authors: University Medical Center, Johannes Gutenberg-University Mainz, I. Medizinische Klinik und Poliklinik, Langenbeckstraße 1, 55131, Mainz, Germany.
authors: Peter R
authors: PR
authors: Galle
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000097:blood; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality; D000077210:Sunitinib
chemical_list: D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D002955:Leucovorin; D005472:Fluorouracil; D000077210:Sunitinib; D002166:Camptothecin
keywords: Chemorefractory advanced gastric cancer; FOLFIRI; Sunitinib; Tyrosine kinase inhibitor; VEGF