Randomized Phase II Placebo-Controlled Trial of Maintenance Therapy Using the Oral Triple Angiokinase Inhibitor BIBF 1120 After Chemotherapy for Relapsed Ovarian Cancer Jonathan A. Ledermann, Allan Hackshaw, Stan Kaye, Gordon Jayson, Hani Gabra, Iain McNeish, Helena Earl, Tim Perren, Martin Gore, Mojca Persic, Malcolm Adams, Lindsay James, Graham Temple, Michael Merger, and Gordon Rustin Jonathan A. Ledermann, Allan Hackshaw, Lindsay James, Cancer Research UK and UCL Cancer Trials Centre, University College London Cancer Institute; Hani Gabra, Imperial College; Iain McNeish, St Bartholemew’s and Royal London Hospital; Martin Gore, Royal Marsden Hospital, London; Stan Kaye, Royal Marsden Hospi- tal, Surrey; Gordon Jayson, Christie Hospi- tal, Manchester; Helena Earl, Cambridge Biomedical Research Centre, Cambridge; Tim Perren, St James’s Hospital, Leeds; Mojca Persic, Derby Royal Infirmary, Derby; Malcolm Adams, Velindre Hospital, Cardiff, Wales; Graham Temple and Michael Merger, Boehringer Ingelheim, Bracknell; Gordon Rustin, Mount Vernon Cancer Centre, Northwood, United Kingdom. Submitted November 23, 2010; accepted May 27, 2011; published online ahead of print at www.jco.org on August 22, 2011. Supported by Boehringer Ingelheim and by University College London (UCL)/ Hospitals Comprehensive Biomedical Research Centre (J.A.L.). An educa- tional grant was also given to the Cancer Research United Kingdom and UCL Cancer Trials Centre by Boehringer Ingelheim to assist with trial coordination. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Jonathan A. Ledermann, MD, Cancer Research UK and University College London Cancer Trials Centre, UCL Cancer Institute, University College London, 90 Totten- ham Court Rd, London W1T 4TJ; e-mail: j.ledermann@ctc.ucl.ac.uk. © 2011 by American Society of Clinical Oncology 0732-183X/11/2928-3798/$20.00 DOI: 10.1200/JCO.2010.33.5208 A B S T R A C T Purpose Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer. We investigated the efficacy and safety of a novel agent, BIBF 1120, a triple angiokinase inhibitor, after chemotherapy for relapsed disease. Patients and Methods We conducted a randomized, double-blind, controlled phase II trial in 83 patients who had just completed chemotherapy for relapsed ovarian cancer, with evidence of response, but at high risk of further early recurrence. The patients were randomly assigned to receive maintenance therapy using BIBF 1120 250 mg or placebo, twice per day, continuously for 36 weeks. End points were progression-free survival (PFS), toxicity, and overall survival. Results Thirty-six–week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P = .06). Four patients continued on BIBF 1120, including two patients for another year or more. The proportion of patients with any grade 3 or 4 adverse events was similar between the groups (34.9% for BIBF 1120 v 27.5% for placebo; P = .49; mostly grade 3). However, more patients on BIBF 1120 experienced diarrhea, nausea, or vomiting (mainly grade 1 or 2 and no grade 4). There was a higher rate of grade 3 or 4 hepatotoxicity in patients on BIBF 1120 (51.2%) compared with patients on placebo (7.5%; P  .001), but this was rarely of clinical significance, and patients continued with the trial treatment. A single-level dose reduction to 150 mg was made in 15 patients, all on active drug. Conclusion BIBF 1120 is well tolerated and associated with a potential improvement in PFS. The observed treatment effect is sufficient to justify further study within a large phase III trial. J Clin Oncol 29:3798-3804. © 2011 by American Society of Clinical Oncology INTRODUCTION Advanced ovarian cancer often responds well to sys- temic chemotherapy, but relapse occurs in most women, and the disease is ultimately fatal. Carbopla- tin and paclitaxel are most commonly used as initial therapy, and many women receive several courses of treatment with these and other drugs at intervals to prolong survival. The length of the gap between treatments is variable but tends to reduce with time. This period provides an opportunity to investigate new disease-modifying drugs. Tumor growth and progression are partly dependent on angiogenesis, and there is good evidence to suggest that angiogen- esis plays an important role in ovarian cancer. 1,2 Many drugs have now been developed to inhibit the angiogenic pathway. These include inhibitors of both the family of circulating vascular endothelial growth factors (VEGF) and the VEGF receptor (VEGFR) tyrosine kinases. 3 BIBF 1120, a 6-methoxycarbonyl-substituted indolinone, is a potent inhibitor of VEGFR, as well as platelet-derived growth factor receptor and fibro- blast growth factor receptor, two important addi- tional signaling pathways involved in angiogenesis. 4 Preclinical studies have shown that BIBF 1120 inhibits vessel integrity and tumor growth. 5 Phase I studies have defined a safe dose with optimal pharmacokinetics us- ing a twice-daily oral dosing schedule. Reversible disturbance of liver enzymes is the dose-limiting JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 29  NUMBER 28  OCTOBER 1 2011 3798 © 2011 by American Society of Clinical Oncology Downloaded from ascopubs.org by 54.204.161.166 on June 7, 2022 from 054.204.161.166 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.