Elsevier

European Journal of Cancer

Volume 49, Issue 18, December 2013, Pages 3831-3838
European Journal of Cancer

Efficacy and safety results from OCTAVIA, a single-arm phase II study evaluating front-line bevacizumab, carboplatin and weekly paclitaxel for ovarian cancer

https://doi.org/10.1016/j.ejca.2013.08.002Get rights and content

Abstract

Purpose

The single-arm OCTAVIA study evaluated front-line bevacizumab plus weekly paclitaxel and q3w carboplatin.

Patients and methods

Patients with newly diagnosed ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] stage IIb–IV or grade 3/clear-cell stage I/IIA) received bevacizumab (7.5 mg/kg, day 1), weekly paclitaxel (80 mg/m2 days 1, 8, 15) and carboplatin (area under the curve 6 [AUC6], day 1) intravenously q3w for 6–8 cycles, followed by single-agent bevacizumab (total 1 year). The primary objective was to demonstrate median progression-free survival (PFS) > 18 months according to the lower 90% confidence limit. Secondary end-points included objective response rate, overall survival, safety and tolerability.

Results

Most (74%) of the 189 treated patients had stage IIIC/IV disease, similar to the ICON7 population. Patients received a median of six chemotherapy and 17 bevacizumab cycles. At the predefined cutoff 24 months after last patient enrolment, 99 patients (52%) had progressed and 19 (10%) had died, all from ovarian cancer. Median PFS was 23.7 months (95% confidence interval [CI], 19.8–26.4 months), 1-year PFS rate was 85.6%, Response Evaluation Criteria in Solid Tumors (RECIST) response rate was 84.6% and median response duration was 14.7 months. Most patients (⩾90%) completed at least six chemotherapy cycles. Grade ⩾3 peripheral sensory neuropathy occurred in 5% and febrile neutropenia in 0.5%. Grade ⩾3 adverse events typical of bevacizumab were no more common than in phase III bevacizumab ovarian cancer trials. There was one case of gastrointestinal perforation (0.5%) and no treatment-related deaths.

Conclusion

OCTAVIA met its primary objective, demonstrating median PFS of approximately 2 years. This bevacizumab-containing regimen is active and tolerable.

Introduction

For more than a decade, standard front-line chemotherapy for epithelial ovarian cancer consisted of 3-weekly carboplatin and paclitaxel [1]. Multiple collaborative randomised phase III trials evaluating the addition of a third chemotherapy agent, maintenance therapy or alternative taxanes failed to demonstrate significant improvements over a standard carboplatin/taxane doublet [2], [3], [4], [5], [6], [7]. Recently, however, three strategies have significantly improved progression-free survival (PFS) and/or overall survival (OS) in this setting: intraperitoneal versus intravenous delivery of cisplatin-based chemotherapy [8], weekly versus 3-weekly administration of paclitaxel [9] and combination therapy with the anti-angiogenic monoclonal antibody, bevacizumab [10], [11].

The Ovarian Cancer: first-line TherApy with beVacizumab, carboplatIn and pAclitaxel (OCTAVIA) study was designed to build on the success of two of these approaches by combining weekly paclitaxel with bevacizumab. Weekly paclitaxel has demonstrated anti-angiogenic properties [12], [13], [14], which may be synergistic with the anti-angiogenic action of bevacizumab. Two large randomised phase III trials – Gynecologic Oncology Group (GOG)-0218 [10] and International Collaboration on Ovarian Neoplasms (ICON)7 [11] – evaluated bevacizumab, 3-weekly paclitaxel and carboplatin followed by single-agent bevacizumab as front-line therapy for ovarian cancer. The two trials differed with respect to bevacizumab dose (7.5 mg/kg in ICON7; 15 mg/kg in GOG-0218), bevacizumab treatment duration (12 versus 15 months, respectively) and patient eligibility (International Federation of Gynecology and Obstetrics [FIGO] stage I–IIa [grade 3/clear-cell] or stage IIb–IV [any grade] in ICON7; stage III macroscopic optimal/suboptimal or stage IV in GOG-0218). However, both trials demonstrated significantly improved PFS with the addition of bevacizumab to standard chemotherapy.

The Japanese Gynecologic Oncology Group (JGOG) randomised phase III New Ovarian Elaborate (NOVEL) trial compared 3-weekly versus weekly paclitaxel, both combined with 3-weekly carboplatin, as front-line therapy for ovarian cancer [9]. The weekly schedule demonstrated significantly improved PFS and OS, although administration was hampered by a high incidence of haematological toxicity, leading to treatment delay or discontinuation in a substantial proportion of patients.

In OCTAVIA, we evaluated bevacizumab, as administered in ICON7, combined with weekly paclitaxel and 3-weekly carboplatin, as administered in NOVEL, but with more stringent criteria for managing haematological toxicity.

Section snippets

Study design

OCTAVIA was a single-arm open-label international study. The primary end-point was PFS according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). For this analysis, new primary lesions were considered as PFS events. Secondary end-points included overall response rate, duration of response in responding patients, OS, time to CA-125-defined progression and safety and tolerability (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0).

Patient population

The trial

Patient population

Between June 2009 and June 2010, 189 eligible patients were enrolled from centres in Russia, Spain, France, Sweden, Italy, Norway, Brazil, the UK and the Netherlands (Appendix). In accordance with the trial design, the characteristics of the patient population were generally very similar to those of the ICON7 population (Table 2).

Treatment exposure

Patients received a median of six chemotherapy and 17 bevacizumab cycles. The large majority of patients completed their planned chemotherapy (Table 3), although many

Discussion

The OCTAVIA study met its primary objective, demonstrating a median PFS exceeding 18 months in patients with newly diagnosed ovarian cancer. The regimen of bevacizumab, weekly paclitaxel and 3-weekly carboplatin was active and well tolerated. Although efficacy estimations in single-arm phase II studies may be less reliable than in randomised phase III trials, the median PFS of almost 24 months is particularly encouraging. A review of recent European phase III trials shows that no regimen has

Conflict of interest statement

Antonio Gonzalez-Martin has acted as a Consultant/Advisor for PharmaMar, Roche and Janssen. Laurence Gladieff, Martin Gore and Sandro Pignata have received honoraria from Roche. Martin Gore and Sandro Pignata have acted as Consultants/Advisors for Roche. Julian Perez Ronco is an employee of F. Hoffmann-La Roche Ltd. Ulrich Freudensprung is an employee of Stamford Consultants AG, working for F. Hoffmann-La Roche Ltd. Sandro Pignata has received research funding from Roche.

Acknowledgements

We thank the investigators and staff at all participating centres. Martin Gore is funded by the UK’s National Institute for Health Research Biomedical Research Centre. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd.

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The OCTAVIA trial is registered with ClinicalTrials.gov identifier NCT00937560.

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