2038 Background: BI 2536 is a novel highly potent and selective inhibitor of the serine-threonine kinase polo-like kinase 1 (Plk1), which is a key regulator of cell cycle progression. Objectives of this trial were the assessment of the maximum tolerated dose (MTD), overall safety, pharmacokinetics and efficacy of BI 2536 given intravenously. Methods: Sequential cohorts of 3 to 6 patients (pts) with pretreated advanced or metastatic solid tumours received intravenous infusions of BI 2536 on days 1 and 8 of a 3-week treatment course following a toxicity guided dose escalation design. Further treatment courses were administered to pts in the absence of disease progression and if toxicity after a 3-week treatment course had resolved. Results: A total of 42 pts was treated at doses of 25 mg (n=3), 50 mg (n=3), 100 mg (n=22), 125 mg (n=5), 150 mg (n=6) and 200 mg (n=3). Reversible CTCAE grade ≥ 3 neutropenia in 14/42 pts represented the main drug related toxicity with an incidence of 3/5 in the 125 mg cohort, 4/6 in the 150 mg and 2/2 in the 200 mg dose cohorts. Dose limiting toxicity (DLT) was defined as drug related toxicity prohibiting administration of the day 8 dose of BI 2536 (hematologic: CTCAE ≥ 3 grade, non-hematologic toxicity: CTCAE ≥ 2). No DLT other than d8 neutropenia was observed. The MTD was defined at 100 mg for the given day 1 and 8 schedule. Further related adverse events (AE’s) were of mild to moderate intensity (CTCAE grade ≤ 2). There were no related AEs resulting in study discontinuation. Preliminary PK analysis showed dose proportionality of C max and AUC 0-∞ with a high clearance (∼ 1500 mL/min) and a high volume of distribution (∼ 2000 L). No accumulation from d1 to d8 occurred. Patients were treated for up to 8 courses without evidence of accumulating toxicity. No objective responses were observed according to RECIST criteria in this heavily pretreated patient population. Conclusions: In summary BI 2536 is a Plk1 inhibitor with a favorable PK and safety profile at the tested dose and schedule. Neutropenia as a mechanism-related toxicity indicates target inhibition in vivo. [Table: see text]
4015 Background: To evaluate the potential role of oxaliplatin in the treatment of patients (pts) with advanced gastric cancer. Methods: Eligible patients had ECOG performance status (PS) 0–2, adequate liver, renal, and haematological function. Pts were randomised to receive FLO: F 2600mg/m2 24h infusion, L 200mg/m2, and oxaliplatin 85mg/m2 every two weeks or FLP: F 2000mg/m2 24h infusion, L 200mg/m2, weekly, and cisplatin 50mg/m2 every two weeks. The primary end point was the 6-month progression free survival rate. A protocol planned interim analysis to evaluate response and safety was performed when 80 patients had been randomized and completed at least one treatment cycle. Results: 105 pts have been randomised. Data on 80 pts were available for toxicity and response (see table). Conclusions: The overall toxicity was low in both arms. The activity of FLO appears promising. Since grade 3/4 non-haematological toxicity affected less than 10% of patients in both arms, no dose adjustments were performed and accrual will continue to the target of 180 patients. No significant financial relationships to disclose.
