University Times

As a clinical researcher at Pitt for more than 25 years, Samuel Jacobs has not lost his enthusiasm for the value of clinical trials in advancing medicine.

"As clinical oncologists we all have a choice to passively watch the process or to be actively involved," Jacobs says. "The research network this University has developed encourages physicians who are active. That is the philosophy here: We have an incredible opportunity to move the research forward and the approach is that we want to be the leader, not wait for others to do the research."

Jacobs is the associate director of clinical investigations of the Oncology Hematology Association at the University of Pittsburgh Cancer Institute (UPCI), which oversees many of the clinical cancer studies conducted at Pitt.

In addition to heading a breast cancer study, Jacobs is the principal investigator for a human subject clinical trial testing a combination of two drugs to treat colon cancer. The national study involves patients at 11 sites under the auspices of the National Surgical Adjuvant Breast and Bowel Project (NSABP).

Jacobs also serves as the NSABP protocol officer for the trial, which means he was responsible for shepherding the protocol — or standard plan — through the approval process of the NSABP and later through Pitt's Institutional Review Board (IRB). (See related story beginning on page 1.)

"What is always a concern of any protocol is the matrix of getting it through the regulatory system," Jacobs says. "One step in this trial was getting approval of the UPCI protocol review committee for science and for safety, which expedited the approvals for the NSABP, and then from there to [Pitt's] IRB.

"In defense of the system, there are five IRB committees, and they get their questions back very quickly, so if you get your responses in very quickly, the process can move unless there are major hurdles. There were no major hurdles in this case."

While it took up to a year to complete the design phase of the study, the whole approval process took less than 60 days, Jacobs says, an unusually short amount of time.

As a phase II trial — testing the effectiveness of drugs in stopping or controlling the growth of cells in a certain type of cancer — Jacobs's study involves drugs that had already gone through phase I testing, which measures dosage safety and side effects.

"In this particular trial, what made it of interest is that there were two drugs that were both known to have activity on one cancer and that had side-effect profiles that were not entirely overlapping," Jacobs says. "Because of the different mechanisms of action and different side-effect profiles, it was a logical sequence to put them together. The next step is to test [the combination] on a specific disease, in this case colon cancer. This is often the way these trials are conducted."

The hope is that the two drugs together will be more effective in treating colon cancer than either one in isolation, he says.

A two-step design "The way the trial is designed," Jacobs says, "there has to be some minimal level of activity in the first step. We want to demonstrate that there is at least 20-25 percent anti-cancer activity among the first 20 patients it's tested on, if it's going to go on to the second step, which would be to test 50 patients."

Jacobs says researchers are loathe to design trials that give inactive drugs to more than a minimum number of patients. "When you have a menu of many potential options, they can all look pretty good in the preclinical evaluation, but you don't know if they work until the clinical trial, and you have to prove they work," he says. "The design of this trial minimizes the number of patients who are initially treated to determine whether there's enough activity to warrant a larger study.

"If there isn't enough activity, well, there are always other things to test," he points out. "But this isn't just a stab in the dark. There is evidence in preclinical investigation that suggests there's a reasonable chance of success."

As a phase II trial, no control group is necessary, Jacobs says. "Everybody gets the same therapy up front; there's no placebo, no 'comparative arm' of the trial. It's a straightforward study looking for a designated response rate among the patients."

He says he expects to have enough data at the end of about three months to make the decision of whether to go on to design step two and recruit 30 more patients.

Recruitment for the study Under the protocol, all participants for the colon cancer study have recurring colon cancer (termed "failed first-line therapy patients") or whose cancer has metastasized, that is, has spread from the colon to another body part. In addition, patients are ineligible if they have taken either of the studied drugs previously.

Recruitment of the 20 patients for step one of the trial has been completed, Jacobs says. "In the case where they failed upfront therapy, they don't have a lot of good options, so this has exciting potential because it offers something that may have efficacy. In the case of metastatic disease, this treatment may be better than what we commonly have available. We don't know that yet, but the treatment doesn't burn any bridges, because if you can have a few bad side-effects from this or you don't respond, you can return to the more standard treatment."

On the other hand, recruiting for an adjuvant trial (testing auxiliary treatments given in addition to the primary treatment) in which there's a standard option and an investigational option is much more difficult, Jacobs says.

"In the adjuvant trial for a newly diagnosed patient that may be potentially cured, with surgery for example, you have the standard therapies and the investigational therapy. The latter usually is a combination of standard therapy with an addition. We have somewhat greater difficulty accruing patients for those trials. They say, 'Maybe I'm going to get side-effects that have not been explored,' or, 'Maybe it won't be as good as the standard therapy.' "Often you're trying to explain the potential benefits to a patient who's confronted with this overwhelming diagnosis to begin with. It's hard sometimes to make decisions under those conditions."

Does Jacobs have a recruitment pitch?

"I would call it an educational process of informing patients: trying to determine what their inherent fears are, what their concerns are, trying to explore those and explain why I think this is a reasonable approach and a safe approach, and explain what mechanisms are in place that act as safeguards," Jacobs says.

"There are clinicians who are very vested in the clinical trials program and try very hard to explain investigational options to patients and encourage their participation, but that certainly takes more time and effort and more patient visits to do that."

What Jacobs does offer is an argument about the general benefit of clinical trials, especially in oncology.

"We're at a really unique time in oncology, where there are not only new concepts, but new tools that have been developed as recently as in the last half-decade," Jacobs says. These tools include a series of monoclonal antibodies — laboratory-produced substances that can locate and bind to cancer cells — that appear to be relatively more specific and relatively less toxic than what has been available in the past.

"The only way to make progress is to put concepts and tools together. You can't get that information from lab testing, or from an animal experiment; it has to be from human research."

Without human clinical research to back up treatments, physicians are opening themselves up to potential problems, Jacobs says. "A number of years ago, medical oncology as a whole was geared towards dose intensity: the belief that more is better. There were some clinical experiences outside of clinical trials that suggested, for example, that breast cancer patients might benefit by very high-dose therapy with bone marrow transplantation. Even though it was not supported by randomized trials, that became very quickly accepted as the way to treat breast cancer."

It took a decade of comparative clinical trials to belie that assumption. "It turned out high-dose therapy in breast cancer is not better than standard therapy. We rushed to a conclusion before the information was in. That underscores how important it is to do things in a step-wise, comparative, thoughtful clinical research trial where you do come out with answers, because our clinical intuition can be wrong."

–Peter Hart