|The Study 15 trial is a phase II trial to examine whether the addition of hydroxychooroquine (HCQ) to chemotherapy can improve progression free survival in patients with small cell lung cancer (SCLC).
Lung cancer, the leading cause of cancer-related death, accounting for nearly 1.4 million deaths worldwide every year, and has an annual incidence of over 41,000 in the UK. 10-15% are SCLC, representing about 4500 new cases per annum in the UK. Compared with non-small cell lung cancer (NSCLC), patient with SCLC are more responsive to chemotherapy (with an objective response rate of about 70-80%) and radiation treatment but relapse quickly with treatment resistant disease. The survival rates are poor, with less than 10% of patients alive by 5 years. In a previous CR UK & UCL Cancer Trials Centre involving 724 patients, the median survival was 10.3 months. The standard first line chemotherapy treatment remains a platinum-based chemotherapy and this has been unchanged for 20 years. Novel active treatment approaches are urgently needed to improve survival in SCLC.
There is increasing interest in targeting autophagy as a means of selectively killing cancer cells. Numerous pre-clinical studies have demonstrated that small molecule inhibitors of autophagy including chloroquine (CQ) and its analogue, hydroxychloroquine (HCQ), enhances the activity of a broad array of anticancer agents. These results have recently led to multiple clinical trials to evaluate autophagy inhibition in combination with conventional chemotherapy.More recently, CQ was found to have tumour vasculature normalising properties, thereby increasing platinum delivery to tumour tissue and improved chemosensitivity. The advantage of using HCQ instead of CQ is less cumulative retinal toxicity issue. Previous preclinical studies demonstrate that HCQ that etoposide are mutually antagonistic. Study 15 will combine HCQ with gemcitabine/carbopatin chemotherapy in the investigational arm to avoid the antagonistic interaction with etoposide. The control arm remains carboplatin/etoposide due to the fact that this remains the Standard of Care for patients at sites throughout the UK. We previously demonstrated carboplatin-gemcitibine is as effective as standard carbo/etoposide and associated with a better toxicity profile and cognitive function. The study 15 trial will therefore investigate whether the combination of HCQ with carboplatin-gemcitibine compared with standard chemotherapy confers additional survival benefit.
Each patient will be randomised between the control arm and the investigational arm. All eligible patients that consent to take part in the trial will be randomised onto the trial and will receive 4-6 cycles of chemotherapy, those randomised to the investigational arm will also receive HCQ alongside chemotherapy for up to 30 months. All patients will be followed up for 36 months after the last trial treatment is administered to the last patient or until death.
The trial will be undertaken throughout the UK in approximately 30 NHS sites. The target accrual is 112 patients. The trial is funded by the London Lung Cancer Group (LLCG), endorsed by Cancer Research UK and sponsored by University College London.