Innovative phase I clinical trials based on patient genotype monitoring

Recent important advances in the field of pharmacogenetics deserve the inclusion of patient genetic profiling in the optimization of antineoplastic chemotherapy and in clinical drug development. The aim of this study has been to define the clinical utility of innovative strategies for phase Ib studies by translating the new emerging discoveries in the pharmacogenetics field into a chemotherapeutic drug management currently used in cancer therapy, trying to obtain the best therapeutic effect both in terms of toxicity and efficacy. For this reason, three phase Ib clinical studies have been designed and conducted at the National Cancer Institute of Aviano (PN): 1)“A genotype-guided phase I study of irinotecan administered in combination with 5-fluorouracil/leucovorin (FOLFIRI) and bevacizumab in advanced colorectal cancer patients”, 2)“A genotype-guided phase I study of irinotecan administered in combination with 5-fluorouracil/leucoverin (FOLFIRI) and cetuximab as first-line therapy in metastatic colorectal cancer patients”, and 3)“A genotype-guided phase I study for weekly paclitaxel in ovarian cancer patients”. In order to obtain the pharmacokinetic data of both irinotecan and paclitaxel, along with their main metabolites, two HPLC-MS/MS methods have been set up. To guarantee the reliability and robustness of the developed methods, they have been validated in accordance with the Food Drug and Administration (FDA) and the European Medicines Agency (EMA) guidance on bio-analytical method validation. The methods were validated by examining the following parameters: recovery, linearity, intra- and inter-day precision and accuracy, reproducibility, limit of detection (LOD), LLOQ, selectivity, matrix effect and stability. The obtained results were very good both for irinotecan and paclitaxel (the former has been already published (Marangon et al., 2015)). The first phase I study (1) has been concluded and demonstrated that in first-line therapy of metastatic colorectal cancer patients with FOLFIRI plus bevacizumab, irinotecan doses higher than the standard dose can be safely administered based on UGT1A1 genotype. Statistical analysis, made to understand the effect of bevacizumab on irinotecan pharmacokinetics, has shown that bevacizumab decreased the AUC of SN-38, the active metabolite of irinotecan. These results have represented the rationale for the second phase I on irinotecan in combination therapy (2), which is still on-going. Although the phase I study concerning paclitaxel (3) is still on-going, preliminary data demonstrate that, also in this case, higher doses than the standard dose can be safely administered based on ABCB1 genotype.