TOTEM

A Phase I/II single-arm trial to evaluate the combination of cisplatin and gemcitabine with the mTOR inhibitor temsirolimus for treatment of advanced cancers, including first-line treatment of patients with advanced transitional cell carcinoma of the urothelium.

Background

The prognosis for patients with advanced urothelial (predominantly bladder) cancer is poor and approximately 4,700 patients in the UK die each year from the disease. Approximately 50% of patients who are fit enough to undergo (cisplatin-based) chemotherapy will respond to treatment. Median progression-free survival for such patients is approximately 8 months and median overall survival 14 months. Despite a recent increase in our understanding of the molecular basis of bladder cancer, there have been few clinical studies using molecularly-targeted compounds in advanced urothelial cancer.

Improved survival

Temsirolimus (Torisel®) is a treatment which limits the growth of tumours and has recently been demonstrated to improve survival in advanced renal cancer. Pre-clinical studies suggest that temsirolimus may be active against urothelial cancer too. This trial aims to assess whether adding temsirolimus to standard gemcitabine/cisplatin (GC) chemotherapy in the treatment of advanced urothelial cancer is a safe and effective treatment for patients with advanced urothelial disease.

Study design

All participants will be administered a maximum of six 21-day cycles of the 3-drug gemcitabine/temsirolimus/cisplatin (GTC) chemotherapy by drip into the arm. The optimum dose and schedule for temsirolimus will be determined in the Phase I stage of the trial by dose-escalation in successive cohorts of 3-6 participants, until the Maximum Tolerated Dose (MTD) is met. Dose escalation will follow strict rules and intra-participant dose escalation will not be permitted. Once the recommended Phase II dose has been identified it will then be given to an expanded group of participants in Phase II.

Recruitment

Up to 42 participants with advanced non-haematological malignancy will be enrolled in Phase I. Patients with advanced TCC of the urothelium may be included, provided they have not had prior chemotherapy for advanced disease. In Phase II, additional participants with advanced Transitional Cell Carcinoma (TCC) of the urothelium will be treated with the three-drug combination, including temsirolimus at the recommended dose determined in the Phase I stage, up to a total of 63 evaluable participants at that dose level. Efficacy data collected in Phase I may contribute to the Phase II data analysis. Therefore, the maximum number of participants that will be treated in the entire trial is 105.