Professor University of Cincinnati Cincinnati, Ohio
Glioblastoma is an aggressive and lethal malignant brain tumor with molecular characteristics that include isocitrate dehydrogenase wildtype, telomerase reverse transcriptase promoter mutations and constitutive amplification of the epidermal growth factor receptor. Median survival of GBM patients is 8 months and with no effective therapeutic options. The advances in developing targeted drugs such as CDK4/6 inhibitors, PARP inhibitors and HDAC inhibitors that have remarkably improved the prognosis for many other malignancies, have thus far not altered the outcome for GBM patients. Some of the formidable barriers include lack of selective targets and limited Blood-Brain-Barrier permeability. Furthermore, despite advancements in pre-clinical drug development experimental strategies, poor understanding of drug availability to the tumor mass and target engagement in patients is a major reason for therapeutic failure. Phase 0/I Window-of-Opportunity clinical trials represent a state-of-the art in contemporary approaches to addressing this critical issue. Such trials have the potential to identify the most efficacious agent in its class and optimize the dosing regimen.
The goals of such trials include drug administration in GBM patients a few days before a scheduled surgery and accessing resected tumor samples on the day of the surgery. This allows a direct measurement of tumoral drug levels and early pharmacodynamic effects from biomarker and gene expression analysis of the resected tumor tissues. While phase 0 studies are non-therapeutic, first-in-human studies that enroll small population (generally 10-12 patients) who are given micro-doses of the investigational agent, such trials can be seamlessly integrated with phase 1 dose-escalation trials which further facilitates evaluation of dose-dependent changes in the tumoral drug levels and the pharmacodynamic drug effects. A modified study design allows for patients to continue as an add-on to the standard of care therapy which may potentially benefit the participating patients. This novel approach provides key mechanistic and quantitative correlations between employed dose and resulting tumor drug concentrations and early pharmacodynamic effects. When combined with data from patient-derived in vitro studies and in-vivo patient-derived xenograft models, and human pharmacokinetics of the drug (including Cmax, AUC, clearance and protein binding) such inference plays a key role in judicious choice of the drug/dosing strategy most likely to be therapeutically effective.
Thus, the Phase 0/I Window of Opportunity Clinical Trial is a unique strategy has not been fully exploited for its advantages which can speed up the development of neuro-oncology drugs.
Learning Objectives:
Make informed-decision for the selection of best in class drug based on estimates of BBB permeability and tumoral accumulation of the drug.
To gain quantitative (tumor drug availability) and mechanistic insights as an integral part of a phase 0/1 dose escalation study assessing safety and tolerability of an investigational agent.
Use gene expression and biomarker analysis to develop a rational basis for combination therapy
combine cutting-edge clinical pharmacology approach that leverages clinical trial, in vitro–in vivo extrapolation and physiologically based pharmacokinetic modeling for selecting the best-in-class neuro-oncology drug and to optimize its dosing regimen for clinical trials
utilize innovative phase 0/1 and Window-of-Opportunity trials to derive the Maximal Tolerated Dose (MTD) or the Recommended Phase 2 Dose (R2PD) of drug for glioblastoma