Behind the Scenes of a Breakthrough

Every new drug and treatment, every diagnostic test or procedure, every screening method and vaccine—essentially every advance in disease prevention, detection, diagnosis and treatment—is the result of a clinical trial. The backbone of the fight against cancer, clinical trials are the bridge from promising research to patient care. At UAB’s Comprehensive Cancer Center, clinical studies are an integral part of the research and treatment programs for every type of cancer.

Producing a new cancer therapy is a long process. It can take 15 years or more, from the initial discovery in a basic science laboratory to the approval of a drug. In between, the therapy must be tested in pre-clinical experiments and translated into a new patient treatment through three phases of clinical studies. Along the way, patients can gain immediate benefits from the findings, including access to the newest, most promising cancer treatments years before they are available elsewhere.  

A Discovery Evolves            
“The biomedical research starts with a very tiny discovery, and people then realize the clinical potential,” says Tong Zhou, M.D., a Cancer Center scientist and professor of immunology and rheumatology. Nearly a decade ago, Dr. Zhou made just such a discovery, which has developed into one of today’s most exciting trials in cancer research. He and his team identified a monoclonal antibody—a genetically engineered protein—that would bind to the receptor on the surface of tumor cells to induce cell death, or apoptosis. The match worked very well, killing cancer cells but preserving surrounding healthy cells.

Dr. Zhou’s initial discovery led to preclinical evaluations, the next step toward a clinical trial. These studies involve extensive research in tubes (in vitro) and with laboratory animals (in vivo) to test a treatment’s therapeutic potential. At this stage, Dr. Zhou developed a mouse antibody called TRA-8. After many tests in vitro and in vivo, the antibody proved very powerful at inducing tumor death (apoptosis) and seemed to be a safe strategy for patients. UAB then collaborated with Daiichi Sankyo Co., LTD, a Japanese pharmaceutical company, to begin preparing TRA-8 to be studied in a human clinical trial.

Dr. Zhou says that it’s “not easy” to move an antibody from the laboratory to the clinic in just five or six years, but his team accomplished it. The end result was CS-1008, a human protein that does the same thing that Dr. Zhou’s original antibody did—it bonds with the “death receptor” and induces tumor cell death. “It’s a perfect example of a translational study, from basic to clinical,” notes Dr. Zhou, adding that his laboratory continues to conduct research on the antibody to support its development as a treatment.  

Tough Tests            
CS-1008 faced its toughest tests once it moved into clinical trials, which occur in phases. “A phase I trial has two goals,” says Andres Forero, M.D., a UAB Cancer Center senior scientist and hematologist-oncologist who led the CS-1008 study. “It must determine the maximum dose that can be given to a patient, and it must evaluate how safe the therapy is.”

He explains that a small number of patient volunteers receive a very low dose of the medication, usually 1/10 to 1/100 of the effective dose  from the animal trials. If those patients do well and don’t experience any problems, another group of patients receive a slightly higher dose; this cycle repeats until physicians are sure they have determined the maximum safe dosage and evaluated the side effects.            
Evaluations of many research agents will end in phase I because they demonstrate a risk to people. In the case of CS-1008, however, Dr. Forero and his team discovered that the human body tolerates it very well, with minimal negative reactions or none at all. In addition, says Dr. Forero, the antibody can be administered in “good doses” that maintain the right amount of the cancer-fighting protein in the patients’ blood. As a result, CS-1008 earned the pass to phase II clinical trials.            

“In phase II trials, you select a disease and evaluate how the medication works against it,” says Dr. Forero. “You already know the dose, and you know what happens in patients; now you want to know how effective it is.” In the preclinical experiments, CS-1008’s predecessor, TRA-8, had been tested in numerous tumors, from breast to colon cancer. Because pancreatic cancer appeared to be among the most sensitive to the drug, the team delivering the agent focused the first phase II trial on that type of tumor.            

UAB opened the trial, which was also offered in different medical centers around the country, and the study enrolled a total of 60 patients. Once again, researchers found that CS-1008 is safe—and that it can be combined with standard chemotherapy. Dr. Forero and his team continue to analyze data from the trial and hope to have their full findings by the middle of this year. Everyone expects good results, he adds.  

Measuring the Benefits            
While therapies typically have only one phase I trial, multiple phase II trials test the treatment against different types of cancer. For CS-1008, “other phase II trials are already under way or are about to start in colorectal cancer, lung cancer, ovarian cancer, and in the very near future, triple negative breast cancer (a tumor with no expression of hormonal receptors or HER-2 that typically does not respond to standard treatments),” Dr. Forero says. “Triple negative breast cancer is the most promising in my mind because it has a very poor prognosis, and our antibody was effective against every triple negative cell line in every animal model with triple negative tumors that we tested.”

In fact, Dr. Forero continues, “of every tumor that we have tested in the last 10 years, triple negative breast cancer is probably the one that will be the best application of the antibody.”            

Following the data analysis from the phase II trials, medications that prove to be effective will move into phase III, where they can benefit large groups of people, often thousands of patients. The goal of this phase is to confirm the therapy’s effectiveness and compare it to commonly used treatments. “That sounds simple and easy,” Dr. Forero says, “but in reality it’s very complicated, with all the regulations, approvals, contracts, and funding support to consider. Unfortunately, it takes between 10 and 15 years for a new medication to move from the lab to the patient.”            

For this reason, enrolling in a clinical trial can often be the most promising option for a cancer patient, Dr. Forero explains. “Many times, patients don’t have 15 years to wait for a drug to be approved. Clinical trials are the only way you can be exposed to new drugs” from the cutting edge of medical research, he says. “There is no doubt in my mind that in this country, the best way for many patients to be treated is through a clinical trial.”