Phase I Multicentre Tax-Torc Trial of the Dual Mtorc1/2 Inhibitor Azd2014 (A) Plus Weekly Paclitaxel (P) in Patients (Pts) with Solid Tumours (Crukd/12/013)

Aim: Activation of the PI3 kinase-AKT-mTOR pathway is hypothesized to contribute to resistance to chemotherapy and targeted agents in many cancers. Enhanced PI3 kinase pathway signaling has been shown in ovarian cancer cell lines and ascitic cells from pts showing chemoresistance. In a previous phase I trial the maximum tolerated dose (MTD) of the dual mTORC1/2 inhibitor AZD2014 (A) as monotherapy was defined as 50 mg bd 7/7. Preclinically, when A is combined with P, additive apoptosis is observed. Therefore, the combination of A and P was evaluated in a multicentre Phase I trial in patients with solid tumours (EudraCT 2012-003896-20). Study aims were to determine the MTD and recommended dose for the combination of fixed dose weekly P with two intermittent schedules of A, based on safety, tolerability, pharmacokinetics (PK) profile, pharmacodynamics (PD) and antitumour activity.