Phase II clinical trials are the clutch moments of translational science, the place where the star medical advances are separated from the disappointing pretenders. Backed by years of promising laboratory findings and a Phase I trial to assess toxicity, a Phase II trial is the first chance for researchers to see whether a new drug or treatment will fly in the real world by showing effectiveness in the patients for which it was intended. Though the number of subjects typically remain in the dozens or low hundreds, a promising result can send the treatment onward to larger trials and (hopefully) eventual approval and acceptance, while a lackluster performance usually sends researchers back to the drawing board.
That tipping point tension was the backdrop for the 15th annual symposium for the University of Chicago Phase II Consortium, a national group of 11 centers working together to recruit patients for cancer clinical trials. Because the specifications for eligible study subjects are often very narrow, casting a wide net for patients allows treatments to be tested faster – and if the trial is successful, to reach approval faster, said Walter Stadler, professor of medicine at the University of Chicago Medical Center and director of the network. Friday’s symposium allowed for a progress report, updating the consortium participants on clinical trials already underway or in the application stage, so that clinicians are aware of trials potentially available to their patients.
The symposium is also a chance to compare notes on how to best design a clinical trial so that a treatment’s effectiveness can best be determined. With speakers from the University of Chicago Medical Center, the University of Michigan, the University of Maryland, and the MD Anderson Cancer Center at the University of Texas, it was a lightning-round survey of what cancer trials look like in 2010 and how the field is changing as personalized medicine inches toward becoming reality. Here are some of the themes I pulled from the symposium – from an outside perspective, these topics seemed to be the big stories going forward in modern clinical trials.
Biomarkers are a Big Deal
Clinical trials, by their very nature, must homogenize a patient population, combining people with different subtypes and stages of disease into the large pools necessary to analyze with statistics. But it is becoming increasingly accepted that most cancers are actually made up of several different diseases with different causes. Furthermore, each of these cancer types will respond differently to a particular treatment. Complicated, yes, but uncovering which treatments are best for each cancer subtype will pave the road to more effective, personalized cancer care.
Those answers may already be hidden in the data of a clinical trial, if researchers can figure out why specific patients respond better to an experimental treatment than others. The best way to do this – for now – is to collect tons of “biomarkers” about each patient – blood samples, genetic information, tumor biopsies, and even clinical measurements. As such, nearly all of the trials described at the symposium included plans to preserve biomarkers from patients that can be used for further study. Michael Maitland, assistant professor of medicine at UCMC, even talked about using potentially harmful drug side effects, such as hyperglycemia and hypertension, as rapid feedback biomarkers to assist in finding the appropriate dose of drug to give each patient.
Personalized Medicine Will Require A New Kind of Trial
While clinicians learn more about using biomarkers to predict which treatment should be given to a particular patient, how those relationships will be empirically tested becomes a larger question. Your textbook example of a clinical trial compares a treatment group to a control group on a chosen outcome, such as disease progression or how long the treatment prolongs life. But when people with different tumors with different molecular profiles are shuttled into different treatment groups, the old Group A vs. Group B comparison will no longer cut it. Such trials will require new, more complex statistics and study design to yield useful answers.
One example of that future was presented by Roy Herbst of MD Anderson Cancer Center, who presented the results of their recently-completed BATTLES trial. BATTLES stands for Biomarker-based Approaches of Targeted Therapy for Lung cancer Elimination, and its design was informed as much by statisticians as clinicians. Using tumor biopsies, genomics, and Bayesian randomization, the trial assigned patients to particular treatments based upon what had been most effective for previous patients with similar biomarkers. The results were presented in the form of a 4X5 table, with no easy take-home message revealed at a glance. But the array of results indicated places where there was indeed more success for specific treatments in specific types of lung cancer – a first small step toward making personalized cancer treatment a reality.
Two Drugs Are Better Than One (Maybe)
The majority of the trials presented and proposed at the symposium did not deal with novel drugs being tested in humans for the first time. Instead, the focus was on combining previously established drugs, in the hope that two weapons against tumor growth would be more effective than a single attack. In part, this strategy was motivated by the complex signaling network of a cell: the Rube Goldberg machine of switches that instruct cells to either grow or self-destruct. Those networks are adaptable, such that merely shutting down one signal may not be enough to stop the uncontrolled growth of tumor cells.
Trials described for head-and-neck cancer, lymphoma, thyroid cancer and more all intended to use combinations of two drugs to try and outflank tumor cells, creating what Tanguy Seiwert, assistant professor of medicine at UCMC, called a “dual targeting synergy.” While such trials carry their own complexities of analysis and design, the hope is that they will prove harder for cancers to evade through drug resistance and evolution.
All Cancers Are Not Alike, Except When They Are
All those drug combinations, presented rapid-fire over 8 hours, started to inspire significant deja vu as the same agents appeared again and again. That was no coincidence – as scientists learn more about the origins of cancer, they’re realizing that tumors that arise in completely different organs siblings in the same molecular family. So agents developed for, say, lung cancer, may be effective in treating cancers of the brain, pancreas, kidney and so on. Drug classes such as VEGF inhibitors (approved originally for colon cancer, proposed for thyroid and head-and-neck cancers) and inhibitors of the Notch signaling pathway (proposed for both pancreatic cancer and melanoma) offered new promise across traditional boundaries of organ systems.