Abstract
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.
