The I-SPY 2 Clinical Trial

For those of you who read the Wall Street Journal, an article appeared in the Friday, October 1 issue that described the I-SPY 2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) clinical trial. This is an adaptive phase II trial designed to facilitate the introduction of new forms of therapy into clinical practice.

The reporter presents the trial as a dramatic advance, suggesting that the era of “personalized care” is finally upon us. I applaud the intent of a trial to apply “window therapy” (i.e. using the window of time before definitive intervention to introduce and test new therapies) to facilitate drug introduction. However, despite the author’s enthusiasm, the design and application of this trial is demonstrably less than meets the eye.

I-SPY2 uses several molecular markers and established prognostics in conjunction with a new molecular profile (mammaprint) to subgroup candidates prior to randomization. The randomization then allows patients to receive either a standard treatment, or one of five investigational drugs combined with standard agents. Sophisticated imaging technologies are used as surrogates for clinical response, while additional biopsies will provide insights into genomic events.

What this trial does not do is utilize molecular markers (beyond those already available to most clinicians) to select patients for therapy. As such, despite the WSJ author’s glowing review, the trial is, at its core, a randomized selection of candidates. While it may enable the investigators to interrogate the tissue biopsies to answer scientific questions of interest, it does so with no immediate benefit to the patients who participate. Indeed, patients who gain benefit (after being randomized to the investigational arm and then receiving a new combination that actually works) receive said benefit by what could best be described as blind luck. The suggestion that this is “personalized care” falls flat when one realizes that a good outcome is nothing more than a chance event!

Truly personalized care represents the application of validated predictive models to select candidates for specific therapies. Good outcomes can then be ascribed to the intelligent selection and application of effective treatments. The cancer research community’s single-minded focus on genomic platforms, to the exclusion of functional platforms, forces patients to continue to participate in “randomized” trials to test hypotheses of interest to the investigators, largely at the expense of the patients in need. These types of advances could be more rapidly made utilizing functional profiles, such as the one offered at Rational Therapeutics.

What these genomic investigators are expecting their patients to say to them is “You may not be able to treat me any better, but I like the way you think.” What informed patients should be saying instead is, “I don’t care how you think. I want you to treat me better!”

The EVA-PCD™ Platform

At the recent meeting of the American Association for Cancer Research (AACR) held in Washington D.C (April 16-21, 2010), the theme remained consistent with the ground swell of interest in personalized care. Many of the sessions reflected the changing paradigm of clinical trials with a growing focus on biomarker analysis and patient selection predicated on genomic and proteomic features. Among the most compelling presentations were those that examined the manifest complexities of human signaling circuits. One presentation by Dr. Neal Rosen from Memorial Sloan Kettering in New York examined redundancy and feedback as principal determinants of clinical response to signal inhibitors. That session, chaired by Dr. Engleman from Harvard Medical School, examined the cross talk between EGFr and PI3K pathways. Using cell line systems, these investigators drilled down onto RNA and DNA expression profiles to examine how inhibitors acting for one pathway might up or down regulate parallel pathways.

This work dovetailed perfectly with our presentation on Monday, April 19, 2010 (Nagourney, R. et. al, Horizontal and vertical signal pathway inhibition in human tumor primary culture micro-spheroids. Abstract 1764, proceedings AACR 2010). In this analysis, we used small molecules tyrosine and serine/threonine kinase inhibitors to examine the points of commonality and disparity in these two crucial signaling pathways to assess how future drug combinations might provide response with these novel classes of agents.

The most exciting aspect of our work is the capacity of the human tumor micro-spheroid platform (EVA-PCD™) to capture all of the operative mechanisms of response and resistance. This, more closely than other platforms, recapitulates the complexity of human tumors and provides insight into these  complex and redundant biological pathways. No genomic or proteomic tool can approximate the clinical relevance of the EVA-PCD™ platforms’ predictions.