A phase II clinical trial of the Vascular Disrupting Agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma
Introduction
Malignant Pleural Mesothelioma (MPM) usually presents with advanced disease, commonly several decades after asbestos exposure. Chemotherapy with pemetrexed and cisplatin is the established first line treatment for advanced MPM [1] and improves survival modestly over cisplatin alone. However, patients invariably progress, and to date there is no established second line treatment. There is a clear need for drug development and clinical trials of second-line therapy in this disease.
Targeting the vasculature of tumours represents a promising cancer therapeutic approach. Tumour microvascular density is significantly higher in MPM than in non-neoplastic mesothelium, or in other tumour types [2], [3], [4]. Increased tumour microvascular density in MPM is associated with a significantly shorter survival [3]. As a result, tumour blood vessels are a potential target for therapy in MPM. Vascular Disrupting Agents (VDAs) destroy tumour blood vessels and present an attractive proposition for therapy in MPM. The properties of tumour endothelium appear to be sufficiently different from normal endothelial tissue, enabling VDAs to be developed that selectively target tumour blood vessels. These agents exert their primary action on the pre-existing blood vessels of solid tumours, in contrast to the anti-angiogenic agents that prevent new blood vessel formation [5].
BNC105P is a pro-drug of BNC105, a small molecule tubulin polymerisation inhibitor that functions as a VDA through selectively shutting down tumour blood vessels without affecting normal vasculature. BNC105 has 80-fold higher potency in inhibiting proliferating as compared with quiescent endothelial cells [6]. Preclinical in vitro and in vivo cancer models have demonstrated significant tumour growth suppression and regression with BNC105P, with a better therapeutic index compared to other VDAs in development such as the combretastatin CA4P [5]. Phase I data determined a maximum tolerated dose of 16 mg/m2 on a day 1 and day 8 of a 21 day schedule [7]. This study also demonstrated in vivo changes in tumoral blood flow using dynamic contrast enhanced MRI, thus reflecting an expected VDA mechanism of action. A dose–response relationship was seen, with reduced levels of polymerised tubulin detected in peripheral blood mononuclear cells when exposed to higher BNC105P doses. Although the phase I trial did not show any objective responses among 21 patients, the best observed response was stable disease up to week 22 in a patient with MPM who had progressive disease at study entry and received BNC105P at a dose of 8.4 mg/m2 [7]. Following this signal for potential activity, this single arm phase II clinical trial investigated the efficacy of single agent BNC105P in patients with progressive MPM after pemetrexed and platinum first line chemotherapy. An additional aim was to identify potential biomarkers of response.
Section snippets
Study design
This prospective, multicentre, non-randomised phase II trial was conducted by the Australasian Lung Cancer Trials Group. The primary endpoint was centrally-reviewed objective tumour response rate (OTRR) as assessed by spiral computed tomography (CT) using the Modified Response Evaluation Criteria In Solid Tumours (RECIST) [8]. Secondary endpoints included progression free survival (PFS), treatment duration, adverse events, and overall survival. Exploratory correlative analysis of serum
Results
Thirty participants were enrolled between July 2010 and April 2011. The analysis of centrally reviewed tumour responses from the first 24 patients triggered the study to terminate recruitment and results from all 30 patients are reported here with a median follow up of 10.4 months. Patient characteristics are displayed in Table 1. The median time from diagnosis to study enrolment was 13.9 months (range 3.2–51 months).
All patients received at least one dose of study drug. The median treatment
Discussion
There remains no accepted second line systemic therapy in MPM. This study of BNC105P in progressive Malignant Pleural Mesothelioma did not meet its primary endpoint, with the majority of patients demonstrating progression shortly after study entry. A single centrally confirmed and prolonged partial response was seen; there were no distinguishing clinical characteristics noted in this patient other than a long period from diagnosis to study entry. This is the first clinical trial to investigate
Conclusion
In conclusion, this study adds to the literature reporting the use of BNC105P in patients with advanced cancer, and confirms the tolerability of the drug in this group. However, the results do not support use of BNC105P as a single agent in this disease. Ongoing laboratory work is examining combinations of BNC105P with cytotoxic chemotherapy in murine xenograft models, including MPM. Phase I/II studies of BNC105P in combination with everolimus as second line therapy in renal cell carcinoma, and
Conflict of interest
Gabriel Kremmidiotis and Annabell F. Leske are employees of Bionomics Ltd. David C. Bibby was an employee of Bionomics Ltd during the conduct and analysis of the study.
Funding support
The study was funded by Bionomics Ltd.
No tobacco industry support has been received for the conduct of this research. None of the investigators involved have received tobacco industry support.
Acknowledgements
We gratefully acknowledge data management assistance from Lucille Sebastian, Xanthi Coskinas, Michelle Cummins; data analysis assistance from Marion Fournier; and initial assistance with the manuscript from Mateya Trinkaus. We also thank Dr Tina Lavranos for her contribution in the biomarker analysis. Finally, we acknowledge other site investigators, staff and study participants.
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