Introduction: Nimotuzumab (Theraloc®) is a humanized antibody (mAb) that recognizes an epitope located in the extracellular domain of the human EGFR. In previous clinical phase I trials in pts with head and neck as well as nasopharyngeal cancer, nimotuzumab significantly improved the effects of simultaneous radiotherapy. In addition, efficacy was demonstrated in a phase II study in children with recurrent high malignant brain cancer utilizing nimotuzumab as monotherapy, and a phase II study in recurrent, locally advanced and /or metastatic pancreatic carcinoma.

Purpose: This study was designed to evaluate the impact of gemcitabine on the pharmacokinetics of nimotuzumab in pts with locally advanced or metastatic PC. The primary objective for PK analyses was the determination of the area under the serum concentration versus time curve (AUC) from end of first infusion (time point: 0 h) up to 168h (AUC0-168h) and the elimination half-life (t1/2) and the maximum serum concentration (Cmax). Secondary objectives were the determination of the trough nimotuzumab serum levels before subsequent infusions of the antibody and the possible accumulation.

Methods: Blood samples were collected prior to first dose, at the end of a 30 to 60 min-infusion, 3h, 6h, 48h, as well as before the second dose at time point 168h. Nimotuzumab was measured by the use of a cellular ELISA and pharmacokinetic calculations were done using the program Kinetica®.

Results: Currently, blood samples from 6 pts were analyzed at the fixed dose of 400 mg nimotuzumab in combination with 1000 mg/m² gemcitabine and compared to the pharmacokinetics of a monotherapeutic treated group (25 pts divided to four dose levels, 200, 400, 600 and 800 mg, respectively). For the 200 mg dose level, the mean value of Cmax was calculated to 149 ± 60 µg/ml (mean ± SEM, n = 22 applications), t1/2 was calculated to 53 ± 19 h, volume of distribution to 1.54 ± 0.58 l, respectively. The total clearance was determined to 22 ± 11 ml/h (n = 22). The trough values after 168 h were 13 ± 9 µg/ml (n = 24). These values changed with increasing the dose up to 800 mg. As a consequence, terminal half life increased about 2fold to 112 ± 38 h (range: 87 to 156 h, n = 3), whereas total clearance was reduced. Conclusions: The pharmacokinetic of nimotuzumab is non-linear. Combined with gemcitabine, the elevated pharmacokinetic parameters at the given dose of 400 mg were in the expected range. The differences in AUC (33945 ± 10090 µg/ml*h (monotherapy) vs. 29488 ± 12641 µg/ml*h (combination with gemcitabine)), t1/2 (83 ± 28 h vs. 108 ± 42 h) and clearance (13 ± 4 h vs. 17 ± 11 ml/h) were not significant. Thus, the results did not show any pharmacokinetic interaction between nimotuzumab and gemcitabine. A randomized first line clinical investigation with gemcitabine vs. gemcitabine + nimotuzumab is planned to start quarter I/2007.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA