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First-line randomized phase 2 study of gemcitabine/cisplatin plus apatorsen or placebo in patients with advanced bladder cancer: The international Borealis-1™ trial

By: Bellmunt J.1, Eigl B.2, Senkus E.3, Loriot Y.4, Twardowski P.5, Castellano D.6, Blais N.7, Sridhar S.8, Sternberg C.9, Retz M.10, Blumenstein B.11, Jacobs C.12, Stewart P.13, Petrylak D.14
Institutes: 1Dana-Farber Cancer Institute, Dept. of Medicine, Boston, 2British Columbia Cancer Agency, Dept. of Medical Oncology, Vancouver, 3Uniwersyteckie Centrum Kliniczne, Dept. of Oncology Radiotherapy, Gdańsk, 4Institut Gustave Roussy, Dept. of Oncology, Paris, 5City of Hope National Medical Center, Dept. of Medical Oncology and Therapeutics Research, Duarte, 6Hospital Universitario 12 De Octubre, Dept. of Medical Oncology, Madrid, 7Centre Hospitalier Universitaire De Montréal-Hospital Notre-Dame, Dept. of Medicine, Montréal, 8Princess Margaret Hospital, Dept. of Medical Oncology, Toronto, 9San Camillo and Forlanini Hospitals, Dept. of Medical Oncology, Rome, 10Technische Universität München, Dept. of Urology, Munich, 11Trial Architecture Consulting, Dept. of Statistics, Washington, 12OncoGenex, Inc., Dept. of Clinical Research, Bothell, 13OncoGenex, Inc., Dept. of Clinical Development, Bothell, 14Yale University School of Medicine, Dept. of Medical Oncology, New Haven

Introduction & Objectives

Heat shock protein 27 (Hsp27) is over-expressed in bladder cancer (BC) and postulated to increase tumour growth, metastasis, and chemotherapy resistance. Apatorsen (A; OGX-427), a novel antisense oligonucleotide, inhibits Hsp27 production and can potentially enhance the efficacy of chemotherapy. This trial was designed to evaluate efficacy and safety of A in combination with gemcitabine and cisplatin (GC) in patients with advanced BC.

Material & Methods

Chemotherapy naïve patients with advanced BC were randomized to GC+A 600 mg, GC+A 1000 mg, or GC + placebo. Patients were stratified by Karnofsky performance status (KPS) and visceral disease. The primary endpoint was overall survival (OS). Prognostic sub-groups were retrospectively evaluated using multiple variable modelling and hierarchical step down. A post hoc analysis was performed to explore the hypothesis that Hsp27 inhibition might be relevant to OS in poor prognosis disease.

Results

A total of 179 patients were randomized/treated. Median OS was 15.2 months (m). When compared to GC + placebo, GC+A 600 demonstrated improved OS and PFS (OS HR = 0.856 and PFS HR = 0.830) versus GC+A 1000 (OS HR = 0.898; PFS HR = 0.927). Results from the post hoc model revealed that KPS, liver metastasis, alkaline phosphatase, and hemoglobin were prognostic. A median prognostic score dichotomized patients into poor and good prognosis groups (50% each group). Patients with poor prognosis treated with GC+A 600 had a greater reduction in risk of death (HR = 0.717) than patients with good prognosis (HR = 1.44). The most significant prognostic factor was KPS ≤80% (35% pts in GC+A 600 vs GC) resulting in HR = 0.50 in favour of GC+A 600. Overall treatment was well tolerated. Most common Grade ≥3 adverse events (AEs) were neutropenia, anemia, thrombocytopenia and hypertension. Frequency of ≥3 Grade toxicities were: 89% (GC), 93% (GC+A 600) and 95% (GC+A 1000). GC+A 1000 had a higher treatment discontinuation rate due to AEs.

Conclusions

Advanced BC patients with poor prognosis benefited from apatorsen 600mg combined with first line GC. Apatorsen may be impacting the intrinsic biology of patients with poor risk factors. Further evaluation is warranted in this patient population.

  • Type: Abstract
  • Date: 12-11-2015
  • Rating: 0,0
  • Views: 458
  • Event: 7th European Multidisciplinary Meeting on Urological Cancers
  • Nr: O1
  • Session: Oral presentations of the best abstracts
  • Location: Saturday, 14 November 2015, 08:50 - 09:30, Auditorium
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