Background: gemcitabine (G) and cisplatin (C) is a standard-of-care, combination chemotherapy regimen for neoadjuvant treatment of muscle-invasive and palliative treatment of advanced bladder cancer (BC). More effective regimens are urgently needed, with no significant improvements on GC in more than a decade. Mammalian target of rapamycin (mTOR) is a rational target for BC therapy, as abnormalities are commonly seen in mTOR’s upstream activators/downstream effectors in the PI3K/AKT/mTOR signaling pathway. We therefore performed a Phase Ib trial, combining escalating doses of the mTOR inhibitor, temsirolimus (T) with GC. Methods: following regulatory and ethical approvals, eligible patients with advanced malignancy were treated with one or more doses of intravenous (IV) T plus fixed doses of IV GC in a 21-day (d) cycle. Previous unpublished data suggest a possible interaction between G and T. We therefore pursued a cautious escalation strategy (see table), as a precaution against excessive toxicity. Results: 14 patients (3 BC, 2 lung, 2 ovarian, 7 other cancers; 7 previous platinum exposure) were treated, at 4 dose schedules in 2 UK centers. There were no treatment-related deaths or SUSARs. Of 14 SAEs, 4 were SARs, in 10 individuals, 7 of whom had received IMP. Addition of 10mg T on d15, then d8&15 was tolerated, but DLTs were encountered when administering three 10mg doses of T, both on d1,8&15 (neutropenia; hypokalaemia) and d2,9&15 (febrile neutropenia; rash). T was omitted because of myelosuppression on d15, cycle 1 in 6/8 patients scheduled to receive 3 doses of T. Conclusions: it has not been feasible to add three, weekly doses of T to GC, even at low T doses, in the patient group tested, because of predominantly hematological toxicity. We plan to amend the schedule to include two doses of T, on d2&9, informed by data from pre-planned PK analyses of patients already treated. ToTem was developed by the UK NCRI Bladder Cancer Clinical Studies Group, sponsored by Cardiff University, funded by Cancer Research UK, and supported by supply of free drug and distribution costs from Pfizer. Clinical trial information: 31546330
