Zoledronic acid in the management of mesothelioma - a feasibility study (Zol-A Trial): study protocol for a randomised controlled trial

Abstract

BackgroundNitrogen containing bisphosphonates such as zoledronic acid (ZA) are known to contain certain anti-cancer properties. These have been investigated in the past in various cancers such as breast, prostate and colon. ZA in particular has shown promising results in pre-clinical studies. We propose a multicentre double-blind randomised controlled feasibility study to assess the recruitment and acceptability of ZA/placebo alongside chemotherapy in malignant pleural mesothelioma (MPM).MethodsPatients will be recruited for a 13-month period from October 2016 to November 2017. Eligible patients will be identified via the regional mesothelioma multidisciplinary team meeting. Those who receive chemotherapy will be randomised to receive either ZA or placebo alongside their chemotherapy. Those who decline chemotherapy will be offered to join the trial on the non-randomised open-labelled arm of the trial. Patients will receive a maximum of six cycles of ZA/placebo, at three-weekly cycles. All patients will be followed up for six months from randomisation.Semi-structured interviews to gather data on acceptability of trial procedures, tolerability of ZA and other relevant information will take place after the participants have completed their six cycles of treatment. For a better understanding about non-participation in mesothelioma trials we also aim to interview those who decline to take part in the trial.DiscussionThe qualitative and quantitative data gathered in this feasibility trial will hopefully pave the way to designing a robust full phase III trial to investigate the potential synergistic effect of ZA and current standard treatment for MPM, cisplatin-pemetrexed combination chemotherapy.Trial registrationISRCTN Registry, ISRCTN45536692. Registered on 9 August 2016. EudraCT no. 2015–004433-26.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2851-9) contains supplementary material, which is available to authorized users.

Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma

“…However, they exhibit also antitumor activity, efficiently affecting both the tumor cells and the surrounding microenvironment, as reported in several recent preclinical and clinical studies [ 18 – 20 ]. In particular, zoledronic acid is used with positive outcomes for breast, prostate, and non-small cell lung cancers [ 21 – 23 ] and it was found active in vitro and in vivo against MPM cells [ 24 , 25 ].…”

Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics

“…A recently completed clinical trial, named AZURE trial, postulated certain beneficial antitumor activity of bisphosphonates against breast cancer in the adjuvant setting in a subset of postmenopausal women who were negative for MAF transcription factor [ 53 , 54 ]. Previously studies have shown that MAF regulates the expression of genes important in breast-to-bone metastasis [ 55 , 56 , 57 ]. We next analyzed the relationship between the levels of MAF and bisphosphonate’s targets in breast tumors.…”

Genetic Screens Reveal New Targetable Vulnerabilities in BAP1-Deficient Mesothelioma

“…This enzyme acts downstream of MVK, and ZA is given to patients with osteoporosis and bone metastasis in the clinic. [24][25][26][27] Keeping in mind the extensive use of ZA in the clinic with low toxicity and a possible drug-repurposing application, we aimed to test its efficacy on mouse mesothelioma cell lines. The long-term colony-formation assays and IC50 curves with ZA treatment in mouse mesothelioma cell lines show that Bap1-deficient cell lines are more sensitive to ZA treatment than the Bap1 WT cell line (Figures 2E and S2I).…”