By Faith Hayden, Senior Writer

From the development of lifesaving drugs such as tamoxifen, imatinib, and trastuzumab to the discovery of gene mutations that cause cancer and the advancement of molecular targeted therapy, clinical research trials are the tools that help demonstrate the validity of benchmarks in oncologic therapy. The framework of those clinical trials—which are generally conducted in three phases—has largely gone unchanged since ASCO’s founding in 1964, but what’s being tested in these trials and the approach to research overall is changing.

There are certain key pieces of information that must be learned before a drug can be introduced into the marketplace: what is a safe dose, what are the side effects, does the drug have anticancer activity, and does the drug benefit patients when compared to the standard of care in their disease? Phase I trials have historically determined safe dosage and potential side effects. Phase II trials test a drug’s anticancer activity, and phase III trials analyze the overall patient benefit. Although these clinical trial parameters have endured, the therapeutic agents that we use, the ways we identify patients to receive those drugs, and the overall methodology around clinical trials have evolved.

“Thirty or 40 years ago, drugs were typically identified through screens done in cell lines where the drug was introduced into a panel of cell lines or into a panel of tumor-bearing mice to determine whether or not the drug had any activity in killing the cancer. If it did, and if it seemed like it could be administered safely to people, the drug was brought into clinical testing,” said Richard L. Schilsky, MD, FASCO, ASCO’s Chief Medical Officer. “Little to no attempt was made to understand how the drug was working to kill the cancer, what its mechanism of action was, or whether it had a specific molecular target.”

From maximum-tolerated to optimal biologic dose

Phase I trials previously took a “sledgehammer approach” to dosing, which was incredibly inefficient, said former ASCO President Michael P. Link, MD, FASCO. The starting dose had to be escalated repeatedly in order to achieve any biologic effect, and those patients treated at the earliest phases of the trial had no way of benefiting from the initial dose. Furthermore, in early phase I trials, the dose was escalated in patients until the toxicity became too great to handle in order to find the maximum-tolerated dose.

“In theory, we don’t dose aspirin to the point where people have stomach bleeding,” said former ASCO President George W. Sledge, MD, FASCO. “If aspirin were a cancer drug and we were running a phase I trial, would we really dose aspirin to the point where people were having severe gastric bleeding? I don’t think so. And yet that’s historically what we’ve done in oncology.”

But now, thanks to novel targeted therapies, phase I endpoints are more reasonable. Instead of trying to achieve maximum-tolerated dose, for example, researchers are trying to achieve optimal biologic dose. This paradigm has evolved for a number of reasons. First,
the drugs themselves aren’t as toxic as they used to be. Second, many modern drugs that target a particular mutation don’t have a dose-limiting toxicity.

“Rather than search for a toxicity endpoint, we now look for some surrogate marker or a real marker if possible,” Dr. Link said. “We’re not looking so much for response, but if a drug is supposed to inhibit a protein, you can see if the protein is inhibited at a particular level, and then you don’t have to escalate the dose forever. You found a dose that achieves what you want pharmacodynamically.”

Improving patient population selection

Patient selection for phase I trials has also changed dramatically thanks to our deeper understanding of the science and our ability to measure molecular aberrations in cancer. It used to be that although phase I trials had an overall societal benefit, the individual benefit was minimal. Phase I trials “used to be broad, all-comer trials within a grab-bag of diseases,” Dr. Sledge said. “Now increasingly we are seeing trials where biomarkers of response are actually incorporated into phase I itself.”

Improved patient selectivity has also made phase II trials more efficient. Instead of using what Dr. Link describes as a “brute-force approach” of enrolling patients on an all-comer phase II trial in a particular (or multiple) disease site, it’s not uncommon for modern-day phase II studies to subset the disease into groups with a particular mutation that are more or less likely to respond to the drug on trial. With more targeted agents available, phase II and even phase I trials will likely incorporate particular molecular aberrations into eligibility criteria.

“The way it used to be is you tried a bunch of different tumors that were likely candidates the drug might work on. And then you gave the drug at a dose that you knew through phase I trials was necessary to get an effect,” Dr. Link explained. “Now, we have much more biologic data to try a drug in diseases where there’s a pretty good chance it’s going to work. Understanding the basic biology of the cancer makes those early-phase studies run much more intelligently, increasing the chances that we will target the right patients with the drug, and therefore increase our chances of finding a drug that will benefit patients.”

Challenges created by success

Our scientific understanding has certainly improved, but it’s also created some unique challenges. Although the promise of targeted therapy is enormous and the opportunity of matching the right drug with the right patient could produce far better outcomes, it becomes more difficult to study those drugs because the patients needed to enroll on trial are suddenly rare populations.

“That is going to require that we do clinical trials differently than we used to,” Dr. Schilsky said. “The paradigm has been the patient has to come to the trial. In the future, we’re going to need to develop a system where the trial finds the patient. That’s going to mean we’re going to need more central Institutional Review Boards [IRBs]. We’re going to have to deliver to the point of care a protocol that’s already IRB-approved with a consent form so the patient can be enrolled immediately and you don’t have to spend time finding a protocol, getting it through the IRB, and then wondering if you’re ever going to see a patient with a rare genetic subtype in the next two years.”

Furthermore, as clinical trials are becoming more complex, they’re becoming more expensive. “There is no question that the price of getting a drug on the market has ballooned enormously over the past two decades, and that’s a limiting factor in getting drugs to patients,” Dr. Sledge said.

The expense is a result of numerous complicating factors, including study size and inflation of the costs of conducting research, but perhaps the biggest financial impact comes from the cost of increased FDA and National Institutes of Health (NIH) regulations. “There is no question that there are more barriers to getting drugs on the market than there were in 1970,” Dr. Sledge said. “That’s not all a bad thing. A fair number of the drugs that went on the market in the early days of clinical trials, when ASCO was a raw youth, weren’t very good. Dacarbazine for melanoma, for example, was a drug that bordered on being a toxic placebo. Under the current system in 2014, no one would have ever approved dacarbazine for melanoma.”

Aspects of FDA and NIH regulations, however, have nothing to do with patient safety and may in fact be harming patients in the long run. “Part of the problem is that, like all systems that were built by accretion, it’s gotten very complex. No one has gone back and tried to simplify things so that it’s more logical and straightforward,” Dr. Sledge said. In addition, research is incredibly risky, and trial sponsors want to minimize the risk. As a result, sponsors (whether private industry or academic institutions) may interpret regulations very conservatively.

“The reason we got so much done in pediatric oncology over 30 years is because the regulatory environment was quite different and wasn’t quite as intrusive,” Dr. Link said. “And one wonders if we would have made so much progress in pediatrics, where we cure 80% of kids now, if we were doing studies in the regulatory environment of today. I think the answer is no, we wouldn’t have.”

Drs. Link and Sledge both point to 30-page informed consent forms “no one reads” as being a particular roadblock to clinical trial conduct. “The output of all this effort has been a huge speed bump in getting things done,” Dr. Link said. “One thing that needs to be analyzed is how much of this is protecting patients, how much is giving us better trials, and how much is bureaucratic nonsense?”

Despite the challenges confronting oncology researchers, the outlook for how we treat cancer is very good, Dr. Link said. “Understanding fundamental biology makes for more rational therapy. That’s our goal. The question is how we get from where we are now to that goal. If we can find out what steps can easily be taken out of the protocol development process without harming patients, without putting them at risk, and without compromising the science of the study, it would be an important advance in terms of what we need to do in clinical trials.”