Elsevier

Lung Cancer

Volume 81, Issue 3, September 2013, Pages 422-427
Lung Cancer

A phase II clinical trial of the Vascular Disrupting Agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma

https://doi.org/10.1016/j.lungcan.2013.05.006Get rights and content

Abstract

BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed/platinum chemotherapy, ECOG PS 0–1, adequate organ function, and measurable disease. BNC105P 16 mg/m2 was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles. No significant haematologic, biochemical, or cardiac adverse events (AEs) were observed. Grade 3 or 4 AEs occurred in 10 patients (33%). There were 2 deaths on study: 1 cardiorespiratory, the other to pneumonia. We observed 1 partial response (3%); 13 patients had stable disease (43%). Median progression free survival was 1.5 months (95% CI 1.4–2.4); median overall survival was 8.2 months (95% CI 3.8–11.9). BNC105P was safe and tolerable. The sole response was insufficient to warrant further research as a single agent.

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.

References (24)

  • G. Kremmidiotis et al.

    BNC105: a novel tubulin polymerization inhibitor that selectively disrupts tumor vasculature and displays single-agent antitumor efficacy

    Mol Cancer Ther

    (2010)
  • D. Rischin et al.

    Clinical, pharmacodynamic and pharmacokinetic evaluation of BNC105P: a phase I trial of a novel vascular disrupting agent and inhibitor of cancer cell proliferation

    Clin Cancer Res

    (2011)
  • Cited by (49)

    • Pleural mesothelioma (PM) – The status of systemic therapy

      2021, Cancer Treatment Reviews
      Citation Excerpt :

      Non-comparative phase 2 clinical trials of single agent anti-angiogenetic therapies, predominantly in chemotherapy pre-treated patients over the years, failed to show meaningful activity. Response rates were modest (0–12%) and median PFS was less than 5 months (Table 1).[50–59] Furthermore, in a large randomized phase 3 trial of 222 patients, maintenance thalidomide after first line platinum-pemetrexed unfortunately did not demonstrate improvement in PFS or OS compared to active supportive care alone (median OS 10.6 months with thalidomide vs 12.9 months with supportive care; HR 1.2; 95 %CI 0.9–1.6, P = 0.21).[60]

    • 4-Hydroxy-3-methylbenzofuran-2-carbohydrazones as novel LSD1 inhibitors

      2020, Bioorganic and Medicinal Chemistry Letters
    View all citing articles on Scopus
    View full text