Methodology for development, validation, and use of novel endpoints in oncology

Project: Research project


Efficient oncology clinical trial design requires optimal endpoint selection. Previous standard oncologic
endpoints of binary dose-limiting toxicity in phase I, dichotomous tumor response in phase II, and overall
survival in phase III are all being appropriately challenged as inefficient, imprecise, or impractical. These
endpoints require reconsideration in the current era, where therapies are increasingly targeted, are sub-
population specific, have non-cytotoxic mechanisms of action, and where, in many diseases, multiple
endpoints or effective lines of treatment exist. In this project we propose 3 highly interactive yet distinct
specific aims related to the development, validation, and implementation of novel endpoints in oncology clinical
trials: 1) novel use of continuous metrics of adverse events (including multiple event types and cycles of
treatment) alone and in concert with preliminary efficacy measures as phase I trial endpoints; 2) new and
refined methods to evaluate potential surrogate endpoints at both the individual patient and trial levels; and 3)
implementation of novel phase II and III trial designs where multiple endpoints and/or predictive biomarkers
exist. Specific Aim 1 will expand existing expertise in adaptive dose-finding designs by incorporating
multivariate toxicity endpoints and using bivariate endpoints incorporating both toxicity and preliminary efficacy
measures. In Specific Aim 2, novel methods for surrogate endpoint evaluation will be developed and
rigorously tested using an already developed robust simulation engine. A novel design proposed by our group,
the first to address the critical absence of implementation strategies for surrogate endpoints through a trial
design making explicit and monitored use of a newly validated surrogate as its primary endpoint, will be
enhanced in Specific Aim 3 to account for multiple putative surrogate endpoints or multiple biomarker-based
subgroups with heterogeneous multi-endpoint performance within a new phase II or III trial. Each aim builds
on existing expertise and strong preliminary data to advance the field in a novel yet practical manner that can
be readily translated into clinical trial practice, taking advantage of the unique data and trial resources available
at the Mayo Clinic. In particular, the research team at the Mayo Clinic under Dr. Sargent's leadership has the
un-paralleled opportunity to directly translate these methodological advances in novel designs and endpoints
into practice through implementation in upcoming oncology clinical trials.
Effective start/end date2/1/141/31/18


  • National Institutes of Health: $296,091.00
  • National Institutes of Health: $265,668.00
  • National Institutes of Health: $322,993.00


Clinical Trials


  • Medicine(all)