Abstract 2746: A phase I, dose-escalation study of the Eg5-inhibitor EMD534085 in subjects with advanced solid tumors and lymphoma

Abstract

Abstract Background: EMD534085 is a potent and selective small molecule inhibitor of Eg5, a microtubule motor protein that is critical for proper spindle formation during mitosis. In preclinical studies EMD534085 causes mitotic arrest and cell death and has shown in vivo anti-tumor activity in several tumor types. Patients and Methods: A phase I dose escalation “3+3” study conducted in patients (pts) with advanced solid tumors and lymphoma. The objectives are to define the Maximum Tolerated Dose (MTD) based on the occurrence of Dose Limiting Toxicities (DLT), determine the pharmacokinetics (PK) and PD effects and obtain preliminary signals of anti-tumour activity. DLTs were defined as grade (Gr) 4 neutropenia of >5 days (d) or associated with fever ≥ 38.5C, Gr4 thrombocytopenia, dosing delay >14 d, Gr ≥ 3 non-hematological toxicity except alopecia, nausea and emesis. Dose increments were 100% until Gr 2 toxicity, 50% until the first DLT and 25% until >1 DLTs. The MTD level was defined as the DL below that at which >1/3 or >1/6 pts had a DLT in cycle 1 and a total of 12 pts were enrolled at the MTD. Starting dose level (DL1) was 2mg/m2 administered as a 1 hour intravenous infusion every 3 weeks. Results: Forty-four pts have been treated, 23M/21F, median age 60 range (28- 86) years. Tumor types: colorectal 8 pts, HNSCC 5 pts, sarcoma 5 pts, NHL 4 pts, mesothelioma 4 pts, NSCLC 4 pts, thymus carcinoma 3 pts, ovarian carcinoma 2 pts, other 9 pts. Eleven DLs have been evaluated: 2, 4, 6, 9, 14, 21, 32, 48, 72, 108 and 135mg/ m2. DLTs consisted of 1/6 pts Gr4 neutropenia of >5d at 108 mg/m2 and 1/6 Gr 4 neutropenia >5d and 1/6 Gr 3 coronary syndrome at 135 mg/m2. The MTD was therefore established at 108mg/m2. Relevant AE reported in cycle 2 included Gr 3 renal failure and Gr 3 coronary syndrome. Common adverse events were in general reversible and their severity was Gr≤2 for nausea, vomiting, dry mouth, asthenia, dysphagia, proteinuria and thoracic pain. Pharmacokinetic analysis was performed for the first 10 DLs. Increases in AUC0- and Cmax are dose-dependent without accumulation in the second cycle. At the MDT dose level (108 mg/m2), geometric mean PK values (n=6) were Cmax = 4731 ng/mL; AUC0- = 85263 ng.h/mL; t1/2 = 41 hrs; CL = 1.27 L/h/m2; and Vss = 72L/m2. Median number of cycles administered per pt was 3 (range 1-16). No tumor response has been reported so far, however disease stabilizations lasting more than 6cy (4 month) have been observed in 11 patients (25%) including SCCHN, messothelioma, thymus carcinoma: Conclusion: The primary objective of the study was achieved; the MTD is 108 mg/m2 i.v every 21 d. The AE profile is characterized by transient hematological toxicity and cardiac events. PK appears linear over the investigated dose range, analysis of pharmacodynamic markers is ongoing. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2746.