Title: Zoledronic acid in the management of malignant pleural mesothelioma - a feasibility study (Zol-A Study)
Funder: Department of Health and Social Care

Abstract: Background: Malignant pleural mesothelioma (MPM) is an incurable primary pleural malignancy with an average survival of 9-14 months and a 3 year survival rate of only 8%. Currently only one form of treatment (Pemetrexed and Cisplatin chemotherapy) has been shown in an RCT to give a survival advantage. But even with this treatment only a further 10-12 weeks of life is gained on average. Due to the toxic side effects of this regime and the co-morbidites of those who are diagnosed with the disease a significant proportion of patients are not eligible for this regimen. Zoledronic acid (ZA) is an n-bisphosphonate that has been used for a number of years to treat bone related pathology such as osteoporosis, Paget s disease and bone metastases in certain cancers such as breast and prostate cancer. Studies in animal models inoculated with mesothelioma cells have been promising showing a survival advantage in those receiving ZA. Animal studies have also demonstrated a synergistic effect between ZA and certain chemotherapy agents such as platinum based chemotherapy regimes in mesothelioma. Despite the encouraging results from animal studies there remains a lack of human trials investigating the benefit of ZA in mesothelioma. This is a drug that is well tolerated wiht minimal side effects and is widely used currently in other disease entities. Aims: We propose a double blind randomised controlled multi-centre feasibility study to investigate the practicality of the trial prior to embarking on a phase III trial. We aim to investigate recruitment rates, suitability of the research plan and extrapolate numbers needed to achieve a clinically and statistically significant difference in the primary endpoint (should a difference exist). Plan of investigation: Patients with a histocytologically confirmed diagnosis of mesothelioma who are offered chemotherapy, with a World Health Organisation (WHO) performance status of 0 or 1 will be our patient population. Those who are undergoing chemotherapy will be randomised to ZA or placebo in a 1:1 ratio. Those who decline chemotherapy will be offered ZA on its own. These patients will form a third non-randomised group. We propose a feasibility study to recruit 50 randomised patients over 1 year. Randomised patients will either receive 4mg of ZA in 100ml of 0.9% saline or a placebo in 100ml of 0.9% saline over a 15 minute period. Patients will receive the infusion within a 24-48 hour window prior to their chemotherapy. Non-randomised patients who accept ZA will have 4mg in 100ml of 0.9% saline every 3 weeks. Potential impact: This feasibility study will have direct bearing on the proposed full study, which is a large scale multi-centre double blind randomised controlled study to investigate the effects of ZA in mesothelioma. The feasibility study will provide valuable information regarding recruitment methods and rates, consent procedures, randomisation success and acceptance, patient derived qualitative information and numbers required to recruit for a statistically significant primary outcome, tolerability of the drug and the robustness of our research plan. The full study will have a signifcant impact in that if successful and a survival benefit with ZA is demonstrated, this would be a fairly safe drug that can be easily administered alongside chemotherapy with minimum side effects, to extend life in mesothelioma patients.

Lay abstract: Malignant mesothelioma is an incurable cancer of the lung lining that usually develops as a result of previous asbestos exposure. This is an incurable disease with an average survival of 9 to 14 months from diagnosis. Treatment proven to prolong life is limited to one form of chemotherapy which only extends life by a few months, on average. Zoledronic acid (ZA) is a licensed drug that is commonly used for the treatment of bone disease, such as thinning of the bone (osteoporosis) and in cases where bone deposits occur from other cancers. This drug has been is use for a number of years with a good safety record. Animal studies in mice have shown ZA may have a role in the treatment of mesothelioma by slowing the disease. It is not a curative treatment but it may have a role in prolonging life. In animal studies where ZA was used in combination with certain chemotherapy regimens there appears to be an even greater effect. Unfortunately at this stage the drug is not licenced in mesothelioma, mainly due to the lack of human studies. We propose a preliminary study to assess the practicality of running a trial to establish the role of ZA in patients who have mesothelioma and are undergoing or eligible for chemotherapy. This preliminary study will give us information required to plan a full study that would assess if ZA in addition to chemotherapy would be beneficial to patients or not. In our study, half the patients will have ZA in addition to chemotherapy and the other half will have chemotherapy alone. Neither the patients nor the investigators will know what treatment they have been allocated until the end of the study. In addition, patients who decline to have chemotherapy will be offered the ZA drug alone.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS