Phase Ia/b study of combination carboplatin, paclitaxel, and ridaforolimus in patients with solid, endometrial, and ovarian cancers.

Abstract

TPS3114 Background: mTOR is a member of the PI3K family. Ridaforolimus (RIDA) is a mTOR inhibitor that has demonstrated tolerability as intravenous (IV) and oral formulations. PI3K/AKT/mTOR signalling is associated with resistance to taxanes. In cancer (ca) cells, inhibition of mTOR signalling counteracts AKT-mediated resistance to drugs inhibiting tubulin. Paclitaxel and carboplatin (PC) have broad activity including endometrial, ovarian, and many cancers. mTOR inhibition with PC has synergistic and additive effects in solid tumors. A common defect in endometrioid ca is mutation of PTEN, causing activation of the PI3K/AKT/mTOR pathway. RIDA improved PFS over hormonal therapy of metastatic endometrial cancer in a randomized phase II study (Oza AM, et al. J Clin Oncol. 2011;29 [suppl; abstr 5009]). In 35 patients in a phase II study of RIDA, there were 7.7% partial response (PR) and 58% with stable disease with median duration 6.6 months (Mackay H et al. J Clin Oncol. 2011;29 [suppl; abstr 5013]). Ovarian ca ultimately develops a phenotype resistant to taxanes that may be overcome with mTOR inhibition. RIDA may therefore potentiate the response of endometrial, ovarian, and other solid cancers to PC. Methods: Patients (pts) with advanced solid ca and measureable disease and up to 3 prior therapies received P (175mg/m2 IV) and C (AUC 5 to 6 mg/ml/min IV) on day (D)1 of each 3-week cycle. RIDA in escalating cohorts of 10-40 mg is administered orally daily for 5 days per week (D1-5, D 8-12, D 15-19) in phase IA cohorts. Samples for pharmacokinetics of RIDA and P and pharmacodynamics (PD) are collected. More than 1 anticipated DLT of thrombocytopenia or neutropenia in the latter part of the cycle shifts the escalation of RIDA to an alternate schedule (D1-5, D 8-12). Escalation continues in a 3X3 design until 40 mg/day of RIDA or MTD. Seven pts have been enrolled; 5 ovarian, 1 endometrial, 1 urethral ca. The second cohort of an alternate schedule has been filled and evaluation continues. Further characterization of tolerability, efficacy, and PD are planned at the MTD in the phase IB expansion cohorts of 15 ovarian/15 endometrial cancers.