Clinical Research

Clinical Research

Clinical Research Nurse IV Jennifer Winkelmann

Smarter, smaller, faster: From cars to computers, it’s the future. It’s also the new paradigm of clinical research at Memorial Sloan Kettering, where we’ve taken transformative steps to bring novel therapies to more patients more quickly.

Paul Sabbatini, Deputy Physician-in-Chief for Clinical Research, has been leading the endeavor. A physician-scientist who cares for women with ovarian cancer, Dr. Sabbatini was appointed in 2013 to support a coordinated effort to expand and streamline MSK’s clinical research program.

Pictured: Paul Sabbatini & Collette HoustonPaul Sabbatini, Deputy Physician-in-Chief for Clinical Research, and Collette Houston, Executive Director, Office of Clinical Research

“Most of the approaches that doctors use to treat cancer today are the direct result of successful clinical trials in the past,” he says. But the times — and our understanding of the biology of cancer — are changing radically. With that, clinical research is also evolving.

“The historical way to develop cancer treatments was
built on an inflexible sequence of clinical trials,” Dr. Sabbatini says. “This methodical progression from phase I to phase III trials advanced the field, but progress has been slower than we would have liked, and in many instances there have been only incremental improvements.” And while clinical trials remain the best way to improve treatments, the rigid trial paradigm has become outmoded in many contexts. “What we need to rethink is the large clinical trial with long follow-up looking for small improvements,” he explains.

In a new era of precision medicine, increasing numbers
of patients can be enrolled in trials of therapeutic agents targeting specific mutations or pathways present in their individual tumors, independent of the type of cancer with which they were diagnosed. This means that new cancer drugs can be tested in smaller trials with fewer patients.

“The key to these trials is that we have become much more nimble in confirming responses early on. In a phase I trial we’re able not only to evaluate safety and get the correct dose but also to get a real hint of efficacy,” says Dr. Sabbatini. “You get answers and you get them quickly.”

To bring these novel therapies to patients more efficiently, Dr. Sabbatini and his colleagues doubled the capacity of the Research Council, which is responsible for the scientific review of trials, and created a second Institutional Review Board (IRB). The IRBs are responsible for approving, monitoring, and reviewing all biomedical research involving human subjects.

[MSK clinical trials] are a real partnership among patients, physicians, and our entire clinical research team.

“We’ve also created a system in which we can track where protocols are in the approval pipeline,” says Dr. Sabbatini. “We have someone dedicated to reviewing that and intervening when protocols fall off track. And in selected protocols, we’ve seen the time-to-activation numbers [which measure how long it takes to get a drug or therapy into a clinical trial] fall. We still have work to do, but that’s our focus as we go forward.”

The Center for Mechanism-Based Therapies (CMBT) provides a venue in which investigators and doctors can begin to align patients that have particular targets with specific drugs.

“In the CMBT we are now able to bring developmental therapeutics [led by physician-scientist Richard D. Carvajal], immunotherapeutics [led by physician-scientist Jedd D. Wolchok], and cellular therapeutics [led by physician-scientist Renier J. Brentjens] under one roof,” Dr. Sabbatini explains.

“Quite literally, the CMBT gathers a large group of people in one room — we meet every Thursday — and provides a venue for discussion for investigators who have phase I trial ideas
or concepts, or for pharmaceutical companies that want to partner with us in developing concepts or trials,” he says. “It’s been very successful both in improving efficiencies of trial conduct and in getting our scientists and clinicians involved in early drug development, which is where we think we can have the most impact.”

The hub of operations of MSK’s clinical research program is the Office of Clinical Research, led by Executive Director Collette Houston. Her staff is responsible for managing all aspects of clinical trial protocols. “This means the development of protocols from initiation through completion, quality assurance, and everything in between,” Ms. Houston says.
The “in between” includes informatics, education, training of the staff that conduct the research, and committee reviews. In addition, her office is responsible for contracting, research billing, multicenter trial management, and research support services to help clinical departments manage their activities.

Dr. Carvajal, Director of the Developmental Therapeutics Program, explains that the program is primarily the small- molecule arm of MSK’s drug development efforts, looking at what have come to be called targeted therapies. Dr. Wolchok’s program studies novel agents that modulate the immune system’s response to cancer. And Dr. Brentjens’ program works on a form of gene therapy in which patients’ own immune cells are genetically manipulated to directly attack tumors.

Pictured: Richard CarvajalDevelopmental Therapeutics Program Director Richard Carvajal
Dr. Carvajal, a member of the Melanoma and Immunotherapeutics Service in the Department of Medicine, is charged with developing and increasing early-phase clinical trials at MSK. He says that historically, patients would be referred to phase I trials only when their oncologists had run out of standard options. But not anymore.

“Because of molecular profiling and having more-precise understandings about the unique biology of individual tumors, we are now able to identify patients with tumors harboring alterations in gene X, to understand the effects of these alterations on tumor growth, and then to match patients directly to trials studying agents that address each specific molecular event,” he says.

As researchers are better able to assemble these genetic profiles — correlating the biology of tumors to treatments — they are seeing dramatic responses in patients who previously have experienced disease growth after a number of prior therapies and who have opted to join an early-stage trial. “So even if there are standard options available,” says Dr. Carvajal, “sometimes we’ll recommend to patients that perhaps we should consider this particular clinical trial.”

Twelve physicians with disease-specific and specialized drug development expertise — along with specially trained phase I clinical and treatment research nurses, technicians, and research and administrative staff — make up the Developmental Therapeutics Program. Each physician has a particular drug development focus, such as cancer metabolics, epigenetics, stem cell targeting, cell cycle targeting, cell signaling pathways, novel chemotherapeutics, resistance mechanisms, or DNA damage repair.

Another significant area in the evolving clinical research landscape at MSK is basket trials. These trials study a drug with a specific mechanism of action that may potentially work regardless of the type of cancer a patient has. So instead of starting with multiple clinical trials in different diseases, investigators begin with one trial — the basket — and one or more targets, and allow patients with different cancers to enroll. If one group shows a good response, physicians can expand the group to immediately assess whether other patients would also benefit.

Traditional Clinical Trials versus Basket Trials
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On the flip side, if a group is not showing evidence of effectiveness, the trial can be closed and patients can move
on to consider other therapies. This can happen quickly, so patients do not lose valuable time receiving a treatment that isn’t working. “We can make decisions much, much sooner than if we used the traditional trial model,” explains Dr. Sabbatini.

“More and more, we’re going to see that drugs will go from phase I directly to phase III clinical trials in terms of the developmental path,” Dr. Carvajal says. “Because we’re now not only looking at toxicity and dosage in these contemporary phase I studies, but also assessing efficacy. We are going to see a decrease in the number of phase II trials conducted. It’s no longer enough just to show we can give a drug at a certain dose safely; we have to show that it does something to help our patients.”

Both men speak movingly of the patients who participate. “It’s truly humbling for us to look at our patients, who are dealing with a serious illness, with many choices to make with regard to therapy, and see how many are willing to enroll in these trials,” says Dr. Sabbatini.

“This is a real partnership among patients, physicians, and our entire clinical research team,” says Dr. Carvajal. “Patients are very selfless. We do this, of course, in the hope that we’re going to help them — and often we do. And patients do it in the hope that they will be helped. But they also do it because they know they’ll help people in the future.”