Clinical trials: The root of progress, the future of excellent cancer care

Aug. 26, 2015

Wes and Alyssa Jones

Wes Jones was running out of time against a rare type of lymphoma. The cancer was outpacing eight separate attempts to treat the disease, evident from the softball-sized tumor growing rapidly across his right shoulder and metastasis to his central nervous system. During his darkest days, Jones, who was 34, got his affairs in order and moved up the date to marry his fiancée, Alyssa Sanko. 

His oncologist, Paul Barr, however had one last idea—a Hail Mary pass in the form of a phase 1 clinical trial.

The results were so stunning that Jones’ story is legendary at UR Medicine’s Wilmot Cancer Institute. Within three days of taking the experimental therapy in the spring of 2011, his tumors shrank, and in eight weeks, they were nearly gone. In 13 weeks, he was healthy enough to endure a stem-cell transplant, and this summer, Wes Jones remains in complete remission.

“The clinical trial saved my life,” says Jones, now 39, a Brighton resident, and human resources director for a Virginia-based company. “Nothing else was working. So, without that trial, I probably wouldn’t be here today.”

Cancer is a complex set of diseases, and clinical trials play a major role in helping scientists methodically gather the evidence to introduce new treatments. A major strength of the Wilmot Cancer Institute is its leadership role in the Finger Lakes region for providing patients access to a local and national portfolio of trials. Just since 2008, Wilmot has seen its clinical trial enrollment soar 128 percent.

And as clinical studies evolve—for example, grouping patients in new ways to provide benefits more quickly—it’s important to have knowledgeable faculty like Barr to serve as head of Wilmot’s Clinical Trials Office. Not only has Barr designed and supervised several lymphoma trials himself, he is plugged into what colleagues at other institutions are doing.

New approaches to clinical trials

As Jones grew sicker, Barr paved the way for him to enroll in a clinical study at the Dana-Farber Cancer Institute in Boston. Later, Barr and his Dana-Farber collaborators would describe Jones’ remarkable story for fellow oncologists across the country in a case report for the Journal of the National Comprehensive Cancer Network.Paul Barr, M.D.

“This is one of my favorite cases of all time,” Barr says. “Not only did Wes experience a great result, but his case perfectly illustrates the value of clinical trials and the way they have changed in recent years.”

Increasingly, clinical studies are being organized to look at the molecular characteristics of tumors and discover whether newer or repurposed drugs can block mutations in cancer genes. Older trials tended to focus on the organ in which the disease started and were designed to look for small differences between two treatments. The evolving approach allows patients with a genetic mutation that might respond to treatment to enroll immediately in an early-phase study that could benefit them.

For example, Jones received the drug crizotinib, which was originally approved by the Food and Drug Administration to treat non-small cell lung cancer. But crizotinib also is known to act on the ALK1 protein pathway, which is involved in anaplastic large cell lymphoma, the type of blood cancer that plagued Jones. Because the ALK1 mutation was the common link between lung cancer and lymphoma, Jones was able to receive crizotinib through the Boston research group. He still takes it as a maintenance drug.

Not all patients will have such a positive experience. And not all patients choose to participate in studies due to other health problems, geography or the burdens of additional testing and hospital visits often required by clinical research.  Still, clinical studies are at the root of scientific progress, Barr says, and they continue to be essential for the development of new and improved treatments using modern technology.

Clinical Trials 101

Clinical trials stem from a need to identify better therapies to treat cancer and its side effects. Because it would be unethical to give new and potentially toxic treatments to patients and simply hope for the best, clinical trials serve as a coordinated, responsible and systematic way to evaluate safety, effectiveness, dose and outcomes.

Institutional protocols and federal regulations are in place to protect patients, to make sure they understand the objectives of a study, and to help patients realistically plan for all possible outcomes, including death. The Research Subjects Review Board at the University of Rochester reviews and oversees all clinical trials to protect the rights and welfare of all study participants.

Trials take place in steps:

Phase 1 trials typically evaluate a new treatment in a small number of patients for safety and dose range. However, many new phase 1 studies are being designed with new enrollment criteria based on the molecular characteristics of a patient’s tumor instead of age, disease stage or prior treatments. Early-phase trials are taking on greater importance, as they include more precise subsets of patients who might benefit from targeted therapies.

Phase 2 trials also evaluate safety and effectiveness, and often recruit a larger number of patients. 

Phase 3 trials are usually designed to confirm a treatment’s effectiveness and to compare it with standard care. The FDA often approves drugs based on data from phase 3 trials, although that method is changing, too.

Then and now
Older trials were often less efficient. For example, oncologists looking for a particular genetic link between a subtype of cancer and a targeted therapy would first have to screen the DNA of dozens or hundreds of patients to find just a couple of potential matches. Modern genomic analysis speeds up that process.

As treatments improve, fewer trials require the use of a placebo (a sugar pill). Placebo-controlled trials are still important because they provide valuable information about side effects of treatment. But they often have cross-over options so that patients who receive the placebo eventually can receive the experimental therapy. However, the vast majority of cancer-related studies today do not use a placebo. Instead, they compare the best standard treatments with standard treatment plus a new drug, or they enable patients with few options left to enroll and receive the latest experimental therapies.

Most patients don’t incur additional costs to participate in clinical trials. The study provides the therapy, and the oncologist bills insurance for office visits, blood tests and other standard forms of care. 

Jonathan W. Friedberg, M.D., M.M.Sc., director of the Wilmot Cancer Institute, emphasizes that perhaps the most important mission for cancer care in the years ahead is to improve patient access and understanding of clinical research. 

“We’re not settling for great care based on today’s treatments,” Friedberg says. “We want to lead the way to the next generation of therapies.”

Friedberg, for example, and Patrick Reagan, M.D., are working with the National Cancer Institute to bring a progressive immunotherapy known as CAR T-cell technology to the Rochester region. Currently, the only places offering CAR T-cell therapy in the northeastern U.S. aside from the NCI are Memorial Sloan Kettering in New York City and the University of Pennsylvania in Philadelphia.

CAR T-cell therapy involves extracting a patient’s healthy immune cells (T-cells) from the blood, then genetically engineering them and expanding them outside the body so they will identify proteins on the surface of cancer cells. When the T-cells are reintroduced into the patient’s bloodstream, they are designed to seek and destroy cancer.

“It’s very exciting, futuristic technology,” Friedberg says. “Not all patients respond and sometimes people have a disease for which none of the treatments will be effective. But after standard care is exhausted, studies like these are often less toxic than conventional therapies and they allow us to watch for responses very closely. And some patients do very well.”

Wilmot is involved in other important national clinical research initiatives:

  • This spring, the NCI launched a revolutionary new study called Molecular Analysis for Therapy Choice or MATCH. It is known as a “basket’ trial. More than 3,000 people nationwide with different types of advanced solid tumors and lymphomas will be enrolled. All patients will undergo DNA sequencing. There are no control groups, and therefore everyone enrolled, with an eligible mutation, will have an opportunity to receive a new drug. Researchers will look for hundreds of mutations that exist among the enrolled patients, and then match them to drugs that are already FDA-approved as treatments for other cancers or illnesses. Wilmot oncologist Marcus Noel, M.D., is designing an arm of the study, hence a “basket,” that would match patients with the non-V600 BRAF mutation to Mekinist, a drug typically used to treat advanced melanoma. The FDA has sanctioned the MATCH study, and could approve drugs based on data from that trial alone.
  • Lung-MAP, also known as Lung Cancer Master Protocol, is being led in the Finger Lakes region by Wilmot oncologist Eric Kim, M.D. This study was specially designed to allow doctors to test a handful of experimental treatments at the same time, based on a tumor’s molecular profile. Lung-MAP patients are placed into the groups that are most likely to benefit them, depending upon their genetic tumor type. Not only does it provide a more personalized option, but the trial was also designed to address an unmet need for new therapies for squamous cell carcinoma, a lung cancer subtype associated with smoking and fewer breakthroughs.
  • The Cancer Control & Survivorship research team at Wilmot is the leader in a nationwide network investigating therapies for cancer-related side effects such as fatigue, nausea, and cognitive impairment known as “chemo-brain.” The NCI designated Wilmot as a research hub for these types of studies, and awarded an $18 million, five-year grant to support that role.

“This is the future of oncology,” Friedberg says. “People are watching these new, large trial networks very closely because if we’re able to spin out effective drugs faster, that will be an incredible opportunity for patients and for the entire cancer field.”

Wilmot and the University of Rochester are uniquely positioned in the region as a source for innovative clinical trials – one of the key factors that makes Wilmot stand out among cancer treatment centers.

Wilmot has about 100 other cancer studies open for enrollment, plus 30 in the planning stages, another 30 that are no longer accruing patients but still have people on active treatment and 19 studies with patients in post-treatment follow-up. Additional cancer studies are open at the UR Medical Center through the departments of Urology (17 trials accruing bladder or prostate cancer patients), Radiation Oncology (approximately 30 open studies), and about 20 more cancer-related clinical studies through Surgery and Neurology. Wilmot also offers many trials for patients at its satellite sites, and is working to expand clinical trial access in the region. In total, several hundred patients are study participants.

The research is as varied as cancer itself. Some studies are very low risk, such as testing the effectiveness of a decision-making tool for patients with early-stage prostate cancer, or evaluating a new mouth rinse for oral infections from head and neck cancers. Others test immune therapies, vaccines, medical devices, or chemical agents designed to target malignancies in new ways.

The field of clinical research is moving fairly quickly, Barr notes, and Wilmot is on track to strategically design homegrown studies in the near future.

For example, one such trial could convert a discovery from the laboratory of Mark Noble, Ph.D., to a clinical study for patients with recurrent glioblastoma, a type of brain cancer. Nimish Mohile, M.D., is working with Noble to design a phase 1 study to evaluate whether the widely used breast cancer drug tamoxifen, coupled with a second therapeutic agent identified by Noble’s team, can control this deadly malignancy.  Earlier research suggests that tamoxifen has additional properties that might apply to other cancers including brain tumors. Noble’s laboratory is working on how to harness these other properties as a viable brain cancer treatment.

“This is exactly the purpose of bench science—to not only answer important scientific questions but to take the knowledge one step further, to benefit our patients,” says Hartmut “Hucky” Land, Ph.D., director of research at Wilmot.

Helping to advance science

Walt StandhartPancreatic cancer survivor Walt Standhart, 70, is among the grateful clinical trial participants at Wilmot. He enrolled through the Department of Radiation Oncology following his cancer diagnosis in December of 2012. After successful surgery, Standhart was randomly assigned to a group that would receive standard chemotherapy plus the drug Tarceva, which was originally developed for advanced lung cancer but has been used to treat other types of cancer.

“Given the opportunity to get an additional therapy—even with uncertain benefits—I figured that I’m already into this and why not? And if it’s helpful to advance science, I was happy to do it,” Standhart says.

A marathon runner before the diagnosis, he was able to ease back onto the trails, first by walking his dog, then jogging and finally running again.

By 2014, Standhart was strong enough to compete in the Rochester Marathon. He also ran several other shorter races, qualifying him for a gold patch marking 200 miles of racing from the Greater Rochester Track Club. Standhart chalks up his good fortune to a variety of factors, including exercise and the clinical trial.

“Patients should be asking their oncologists about clinical trial options when they get a cancer diagnosis and then every time they discuss a new therapy,” Barr says. “Our goal is to make sure every patient has the opportunity to enroll if they wish.”