Compressing drug development timelines in oncology using phase '0' trials

Abstract

The optimal evaluation of molecularly targeted anticancer agents requires the integration of pharmacodynamic assays into early clinical investigations. Phase '0' trials conducted under the new Exploratory Investigational New Drug Guidance from the US Food and Drug Administration can provide a platform to establish the feasibility of assays for target modulation in human samples, evaluate biomarkers for drug effects and provide pharmacokinetic data. Phase 0 trials could facilitate rational drug selection, identify therapeutic failures early, and might compress timelines for anticancer drug development. We expect that such trials will become a routine part of early-phase oncological drug development in the future.

Considerations for the use of plasma cytokeratin 18 as a biomarker in pancreatic cancer

“…Conventional chemotherapy regimens incorporating either 5-FU or gemcitabine typically result in only modest improvement in overall survival (Sultana et al, 2007). One of the key challenges in accelerating improved cancer therapeutics is the identification of biomarkers to enable early objective assessment of tumour responses to chemotherapy (Kummar et al, 2007).…”

“…Conventional chemotherapy regimens incorporating either 5-FU or gemcitabine typically result in only modest improvement in overall survival (Sultana et al, 2007). One of the key challenges in accelerating improved cancer therapeutics is the identification of biomarkers to enable early objective assessment of tumour responses to chemotherapy (Kummar et al, 2007).Necrosis of malignant and normal epithelial cells cause release of cytokeratin 18 (CK18) (Kramer et al, 2004), a type I intermediate filament protein and a component of the intracellular cytoskeleton (Fuchs and Weber, 1994). Caspase-mediated cleavage of the CK18 contributes to the degradation of the intracellular cytoskeleton if epithelial cells undergo apoptosis (Leers et al, 1999).…”

Combining Targeted Therapies: Practical Issues to Consider at the Bench and Bedside

“…For example, an EGFR inhibitor plus dasatinib versus an EGFR inhibitor plus a MET inhibitor, with the endpoint being overcoming resistance to EGFR inhibitors. A similar objective could be achieved with a phase 0 trial combining targeted therapies for biomarker testing (for this, the doses of both drugs of the combination must be well known, there must be no expectation of interaction between the drugs, and the biomarker must already have been validated) [63,64].…”

Clinical Trial Phases

“…These trials are before the traditional dose escalation, safety, and tolerance studies, do not replace the Phase I clinical trials and do not indicate whether a therapy has a positive impact on the targeted pathology. These studies help in eliminating candidate therapies before they reach Phase I studies [25]- [27]. These trials were developed to shorten the critical path for drug development, to explore pharmacokinetic and pharmacodynamic profiles of IND's in humans, to help in accelerating identification of promising drugs, and to reduce development time and costs.…”