470PA PHASE I STUDY OF ERIBULIN AND GEMCITABINE IN PATIENTS WITH AVANCED SOLID TUMOURS. A STUDY OF THE PRINCESS MARGARET PHASE II CONSORTIUM

ABSTRACT Aim: Gemcitabine, a nucleoside analogue, and eribulin (E7389), an investigational tubulin-based anti-mitotic drug exhibited synergistic cytotoxic effects pre-clinically and were combined in a Phase I dose finding clinical trial. Methods: A phase I clinical dose-escalation study of these 2 drugs in combination was initiated in patients with advanced solid tumours who had received up to two prior chemotherapy regimens for metastatic disease (CP cohort). Dose escalation was performed in a 3 + 3 design to identify the recommended phase II dose (RPTD). Two additional expansion cohorts consisting of women with gynecologic cancers at the recommended phase II dose (G cohort), and further dose-escalation of chemotherapy-naive patients (CN cohort), were evaluated. Results: Forty five patients were treated in 3 cohorts - 21 (CP), 10 (G), and 14 (CN). The initial combination of eribulin and gemcitabine was administered on days 1, 8, 15 of a 28 day cycle (CP) but due to 2/6 DLTs, a less dose-intense schedule with the 2 drugs given days 1 and 8 on a q21day cycle was assessed. Dose Dose Level N Schedule E7389 (mg/m2) Gemcitbaine (mg/m2) DLT Toxicity 1 (q28) 6 D1,8,15 q28d 0.7 800 2 Thrombocytopenia 1 (q21) 3 D1,8 q21d 0.7 800 2 3 D1,8 q21d 0.7 1000 3-CP 6 D1,8 q21d 1.0 1000 1 Neutropenia 3-G 10 D1,8 q21d 1.0 1000 4-CP 3 D1.8 q21d 1.4 1000 2 Diarrhea; fatigue 4-CN 7 D1,8 q21d 1.4 1000 1 Elevated transaminases 5-CN 5 D1,8 21d 1.6 1000 6-CN 2 D1,8q21d 1.8 1000 1 Neutropenia The RPTD was at dose level 3. No other significant hematologic or non-hematologic toxicities were observed with the CP patients. For the CN cohort, additional escalation at dose levels 4, 5, and 6 was attempted, but due to dose limiting neutropenia seen after Cycle 1, DL3 remained RPTD. Objective responses were seen in all three cohorts – 2/21 (CP), 1/10 (G) and 2/14 (CN). Conclusions: The combination of eribulin and gemcitabine was well tolerated with preliminary evidence of activity being seen. Phase II investigation of this regimen should be considered at a dose of 1.0mg/m2 eribulin and 1000 mg/m2 gemcitabine day 1 and 8 q3 weeks. Support by contract HHSN261201100032C/NO1-CM-2011-00032. Disclosure: All authors have declared no conflicts of interest.