Significant proportion of patients (pts) with adenocarcinoma of stomach (ADCS) present with advanced disease. Paclitaxel (P), either alone, or in combination with carboplatin (C) is well-tolerated, but has modest activity in ADCS. The PI3K-Akt pathway played an important role in cell proliferation and apoptosis in pre-clinical ADCS models. Everolimus (E) is a potent inhibitor of mTOR, a downstream mediator of the PI3K-Akt pathway. Combining chemotherapies with mTOR inhibition may improve outcome
A single-arm, dose-escalation study of E, in combination with P and C (E+PC) was conducted in pts with metastatic and/or loco-regionally advanced ADCS [NCT01514110]. In the phase 1 portion (P1P), the maximum-tolerated dose (MTD), recommended phase 2 dose (RP2D) and safety of E+PC, were determined using a standard 3 + 3 design. Starting dose (dose level I) was E 5mg/d, P 175mg/m2 and C AUC5 every 3 weeks. Dose-limiting toxicities (DLT) were defined as grade 4 haematological or grade 3 or 4 non-haematological toxicities. Preliminary efficacy of E+PC in pts with ADCS, defined by clinical benefit rate (CBR) (CR+PR+SD for 6wks or more as per RECIST), and survival were determined in the phase 2 portion
30 pts were enrolled (P1P = 12) from Jan 2008 to Nov 2014. In the P1P, 2 DLTs (G5 GI bleeding and G3 joint pain) were experienced at dose level II, thus establishing dose level I as the MTD and RP2D. 21 pts were treated at RP2D. Baseline demographics of phase 2 portion: M/F: 9/12, Median age 54 (range 40-69), ECOG PS 0/1/2: 10/10/1. Prior lines of chemotherapy 0/1/≥2: 7/12/2. Median cycles: 6 (range 1-19). Common related ≥G3 adverse events (AEs) include (%): neutropenia (48%), anaemia (43%), thrombocytopenia (29%), mucositis (10%). Febrile neutropenia occurred in 10% (n = 2) of pts. 18 pts were evaluable for response (5 PR, 9 SD, 4 PD). CBR 77.8% (95% CI 58.6-97.0%). Median PFS and OS was 6.9 and 9.0months (95%CI 3.5 – 7.6; 3.8 – 15.1months) respectively
E+PC administered at RP2D was well-tolerated. Comparing with prior reported series of PC alone, E+PC showed more favorable efficacy and has promising activity in pts with advanced ADCS. Acknowledgement- Supported by Novartis Pharmaceuticals Ltd
Clinical trial identification
Legal entity responsible for the study
The Chinese University of Hong Kong
Novartis Pharmaceuticals Ltd.
H.H. Loong: Research Funding: MSD. Advisory: Novartis, Roche. Travel Support: Abbvie, Bayer, Bristol-Myers-Squibb, Novartis, Roche. Speakers Bureau: Abbvie, Bayer. W. Yeo: Advisor: Novartis, Eli Lilly. All other authors have declared no conflicts of interest.