Genomics-based early-phase clinical trials in oncology: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies.

The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force discussed incorporation of genomic profiling into early (Phase I and II) clinical trials in oncology. The task force reviewed the challenges of standardising genomics data in a manner conducive to conducting clinical trials. Current barriers to successful and efficient implementation were identified and discussed, as well as the methods of genomic analysis, the proper setting for study and strategies to facilitate timely completion of genomics-based studies. The importance of properly capturing and cataloguing outcomes was also discussed. Several recommendations regarding the use of genomics in these trials are provided.

Design and conduct of early clinical studies of two or more targeted anticancer therapies: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies.

The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force considered aspects of the design and conduct of early (phase I and II) studies of combinations of molecular targeted agents during their 2012 meeting. The task force defined necessary non-clinical data, such as evidence of additive or synergistic effects in multiple molecularly credentialed and validated models, and appropriate pharmacodynamic marker development. A robust hypothesis was considered critical while non-clinical pharmacokinetic studies were also considered valuable. Clinical trials should include clear objectives that will prove or disprove the hypothesis. Predictive biomarkers/classifiers should be explored in phase I studies, rather than used to select patients. Trial design should be efficient and flexible rather than based on a strict progression from phase I to II to III; researchers could consider phase I studies with an expansion cohort, Phase I/II designs or phase II studies with a safety run in. Pharmacokinetics are recommended when interactions or overlapping toxicity is expected. Pharmacodynamic evaluations should be considered especially in a subset of patients closest to the recommended dose; an attempt should be made to validate surrogate tissues to enable inclusion for all patients. Schedule and or dose should be formally explored for e.g. with a randomised or an adaptive design. Data and knowledge sharing was strongly recommended, including the creation of formal or informal consortia of laboratories with individual expertise in pathway or target based models, collaboration between companies to ensure that agents which are 'best in class' are combined, and the development of databases which will be able to inform the development of future recommendations/guidelines.

Targeted agents: how to select the winners in preclinical and early clinical studies?

There has been a significant shift within oncology drug development away from empiric screening of cytotoxic compounds to the era of genomics and molecularly targeted agents. The drug development process is evolving with greater emphasis on proof-of-mechanism studies in both preclinical and early clinical development. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Task Force, established as a forum for academic and pharmaceutical leaders to discuss methodological issues in targeted anticancer therapy development, met in March 2010 to review what were the minimal data required to make appropriate decisions about moving new targeted cancer agents from late preclinical development into phase I and from phase I into phase II trials. A number of specific questions were posed, and responses to each developed through survey, literature review and discussion at the face to face meeting of the MDICT Task Force. Consensus emerged around the necessity to demonstrate proof-of-mechanism and obtain information on key pharmacokinetic aspects of drug behaviour in late preclinical and early clinical trials. However, controversy remains on the extent of in vivo anti-tumour efficacy required to support clinical development of targeted agents. A systematic review of the data in this area would be informative. Further, while objective response in phase I trials may be a favourable signal about the potential activity of a new agent, debate exists around the weight that should be placed on the observation of stable disease or functional imaging changes in driving drug development decisions in the absence of observing either responses or convincing pharmacodynamic data in phase I. MDICT made a number of recommendations that may aid in future development of targeted agents.

Phase 0 clinical trials: recommendations from the Task Force on Methodology for the Development of Innovative Cancer Therapies.

The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force has been established as an expert forum to develop practical guidance on the development of innovative anticancer agents, in particular targeted agents. The task force recently addressed the utility, design and application of Phase 0 clinical trials in anticancer drug development. It was concluded that the role of non-therapeutic Phase 0 trials is controversial for several reasons, including the lack of clinical benefit for participating patients. However, it was recognised that Phase 0 trials provide an opportunity to generate essential human pharmacokinetic and pharmacodynamic data earlier in the drug development process, which could be a major advantage in the design and decision making concerning further clinical development of an agent. Construction of a 'decision chart' was highly recommended to assist investigators and sponsors in determining whether an agent is suitable for evaluation in a Phase 0 trial.

Design and conduct of phase II studies of targeted anticancer therapy: recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT).

The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force considered aspects of the design and conduct of phase II studies for molecular targeted agents during their 2007 meeting. The task force recommended that multinomial endpoints and designs should be considered for phase II studies of targeted agents, that both single arm as well as randomised designs remain appropriate in certain settings, and that further assessment of novel endpoints (tumour growth kinetic assessment, biomarker or functional imaging) and designs (randomised discontinuation or Bayesian adaptive design) be encouraged. The MDICT cautioned on the use of small randomised trials which have a number of statistical pitfalls and dangers and strongly encouraged the complete reporting, including negative trials, in the scientific literature.

Endpoints and other considerations in phase I studies of targeted anticancer therapy: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies (MDICT).

Oncology drug development has seen a paradigm shift in the past decade from traditional cytotoxic agents to molecular targeted therapies. Given the different mechanisms and toxicities of these agents, drug development methodology may also require novel approaches. To address emerging issues in oncology drug development the 'Methodology for the Development of Innovative Cancer Therapies' (MDICT) task force was established to provide a forum for academic leaders involved in cancer drug development to discuss methodological issues inherent to the study of targeted anticancer therapy. At the inaugural MDICT meeting in 2006, discussion focused on the most appropriate primary endpoints for first-in-man phase I studies of targeted anticancer agents and organisational issues of such studies. This report summarises the scientific reviews and discussions as well as the recommendations regarding phase I trial design formulated by the MDICT task force.