Making Clinical Trials More Efficient, Informative, and Effective

Deputy Physician-in-Chief for Clinical Research Paul Sabbatini

Deputy Physician-in-Chief for Clinical Research Paul Sabbatini

A recent op-ed in the New York Times by journalist and cancer advocate Clifton Leaf asked the question, do clinical trials work? The answer is a straightforward yes. A clinical trial is a tool that when correctly employed can identify more-effective treatments for patients with cancer and other diseases.

It is important to acknowledge that some clinical trials have not been as informative as we would like. Some have shown “improvements” that might not be considered groundbreaking. But others have truly changed the standard of care for a given disease in a single day.

The questions today are, how do we increase the number of informative trials that can change practice and save lives? How do we evaluate promising therapies in the shortest possible time? And when do we stop and move on when the results are not as positive as expected? A well-designed clinical trial can accomplish these goals.

My colleagues and I are focusing on streamlining our clinical research program, which will allow more patients to participate in more trials, and also bring novel compounds and therapies to those who can benefit from them in a timely manner. At Memorial Sloan Kettering, patients and researchers are typically involved in more than 900 total clinical trials at any given time.

The Traditional Paradigm

The standard approaches for developing most cancer treatments have been built on a rigid sequence of clinical trials. Historically these studies advanced the field slowly over time with incremental improvements. Each step reset the benchmark to which subsequent treatments were compared. This approach served us for many years as standard chemotherapy agents with broad applicability across many patients and diseases were being developed.

The development of agents such as cisplatin, carboplatin, and paclitaxel all occurred in this way and these agents still form the backbone of many cancer treatments.

The traditional paradigm of evaluating agents required them to move through phase I, II, and III trials, often over a protracted period of time. The phase I trial was intended to establish a dose — the “maximum tolerated dose” — and to establish safety. These phase I trials were generally small, and an assessment of the effectiveness of the agent was usually not the goal.

The next step involved a phase II trial classically with 35 or so patients enrolled to see if a certain group of patients would have tumor shrinkage and for what period of time. We often accepted a rather low number of patients showing improvement as evidence of activity.

If results of the phase II trial were positive, the investigation would move to randomized phase III trials with large numbers of patients, known in clinical trials as cohorts. Large numbers are required to detect a difference between a new and old treatment, particularly if the differences are expected to be small. Phase III trials often are done at many medical centers around the nation, and sometimes around the world, making orchestration complex, and the time required to get results can be long.

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Rethinking the Large Trial

Just as the computing tools we used five years ago would seem completely inadequate to support us now, the rigid clinical trial paradigm described above has also become outmoded in many situations. Clinical trials remain the best way to improve cancer treatments, but what we need to rethink and avoid is the large clinical trial with long follow-up looking for very small improvements. (Several examples were discussed in the op-ed by Mr. Leaf.)

In particular, this approach will not serve us well in the era of mechanism-based or targeted therapies in which the therapy being tested may only work in a small group of patients but may be highly effective in that group.

The idea of aligning patients who carry a specific therapeutic target with a specific drug has resulted in higher response rates than have been previously seen, and now combination therapy is being considered to overcome the resistance that tumors often develop to anticancer drugs. New cancer drugs are initially tested in phase I trials, but we have become more nimble in confirming these responses early on rather than moving down the traditional paradigm.

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The Basket Trial

The development of the “basket” trial is one example. Instead of starting with multiple clinical trials in different diseases (which requires duplication of regulatory and infrastructure efforts), we start with one trial — the basket — and one or more targets, and allow patients with multiple diseases to enroll in cohorts or groups.

If one group shows good response, we expand this group to immediately assess whether others could benefit from the new therapy. If another group is unfortunately not showing evidence of effectiveness, this group may be closed and the patients can move on to consider other therapy. In this way, the exploration of the effectiveness of a treatment occurs early, quickly, and in one trial.

The optimal phase I trial today often explores drugs with innovative mechanisms. When a robust response rate is seen and the group is expanded sufficiently (called an expansion cohort), this can sometimes bring enough confidence of effectiveness in the phase I trial that smaller randomized trials can be immediately done to confirm the findings.

For example, a recent Memorial Sloan Kettering study of nivolumab and ipilimumab in patients with advanced melanoma, conducted by medical oncologist Jedd Wolchok and colleagues, was expanded so that 53 patients received the combination therapy in the initial trial. In this study, 53 percent of patients had significant reduction in tumor size by 80 percent or more. This trial rapidly confirmed the activity of this combination without having to go to a traditional phase II trial.

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Smaller, Smarter Trials

There are two ways to increase the likelihood that a new treatment shows benefit in contemporary clinical trials. The first is to align the right patient with the right target in trials of therapeutic agents that target a specific mutation or pathway. The second is to identify biomarkers for response — for example, an abnormality measurable in the blood or detectable in the tumor specimen that when present can predict response to a particular agent — as a critical part of new drug development. In this way, we can give a new treatment to those people who are most likely to benefit.

We also need to continue to develop new statistical designs. One of these is called the Bayesian approach, where treatment arms in a given trial are frequently reviewed. The ones that are better performing will enroll more patients, and those doing less well get closed as soon as possible.

We are essentially moving toward smaller and smarter trials looking for clearly meaningful improvements. This allows us to evaluate strategies faster and, most importantly, increase the chance of benefit for individual patients.

When a clinical trial is well designed — whether the results are positive or negative — we learn important next steps. In addition, if we can match the right patient to the right trial, the number of successful approaches will continue to rise.

The clinical trial remains our best tool to identify new therapies, but as with all tools, innovation is required if trials are to remain relevant. We have more novel agents and approaches to consider than ever before, and well-designed clinical trials remain the best way forward.

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Paul Sabbatini is a medical oncologist caring for women with ovarian cancer. In his role as Deputy Physician-in-Chief for Clinical Research he is responsible for developing and expanding Memorial Sloan Kettering’s clinical research program.


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It seems to me that another fundamental objective of the clinical trials should be to identify the parameters that make the treatment work for some patients and not for others. It would seem that the answer to that question would be a breakthrough.

In 1998, I was in CLBG 9082 (I think - developed at Duke) for breast cancer for women with 10 or more positive lymph nodes. I was randomized into the higher chemo arm, with autogolous bone marrow replacement and 3 weeks in intensive care. I had 17 nodes positive, 4 tumors, my pathology was off the charts and neither Herceptin or estrogen drugs would work for me. That was 15 years ago. The trial was hard and long, but I am here today, which I truly don't believe I would be without it. It was out of Dana Farber and I received the best care and continual testing (CT scan, Bone Scan etc) for 7 to 8 years later, until my oncologist was finally able to convince me I could atop the annual tests. A clinical trial saved my life, so thank you to all the researchers who made my trial happen and those who continue to develop trials today. I hope my cancer never comes back, but if it does, I will be the first in line for a trials.

Thank you for this information. It makes sense plus it get effective medication to the suffering more quickly.

As a patient and a nurse who has Non-Hodgkins Lymphoma I think one of the problems recruiting patients to trials is that the patient must have had no prior treatment with chemo. Most patients are so shocked by the fact that they are diagnosed with cancer they do whatever their doctor suggests which frequently is either chemo or radiation. If their cancer returns and they want to enter a trial they are not usually eligible. I understand the reason for enrolling people whose disease is free of other agents but there should be someway of setting up these studies to allow for prior treatment.

Patricia, thank you for your comment. We agree that a variety of clinical trials are needed in order to offer the most patients the opportunity to participate. Some clinical trials do limit the number of previous therapies either because the investigational treatment has the potential to work best if other treatments have not been given, or there is concern about side effects in patients who have received multiple other drugs. We and others now have many clinical trials, however, that allow for a number of prior treatments. Some have no restriction at all. We encourage patients – even with multiple prior treatments – to discuss the possibility of clinical trials with their physicians if appropriate.

Very informative and much appreciated article.
I have a question regarding a trial that was removed as the drug was argued over and held up in court between the Henry Jackson Foundation and Norwell Inc. It was hugely successful in phases 1 and 2. The GP2 vaccine. I am a metastatic breast cancer patient with grade 3 overexpression which responded to GP2 with zero recurrence. You can imagine my dissapointment, as a mother of 5 young children, 3 adopted with special needs, when this amazing vaccine was pulled. I was one of a group of people that petitioned that the vaccine be released and to our relief we stopped the case from being appealed again. As I am now in the position to receive the vaccine, before recurrence, I am anxious to know if GP2 or any other similar peptide vaccine will be available for trial in the near future.
I anxiously await your reply. Thank You.

Dear Kathleen, we’re sorry to hear about your diagnosis. MSK is not offering GP2 as part of a clinical trial, but you can check with other centers participating in the trial on the National Cancer Institute’s website to see if and when they plan on resuming their recruitment:

If you would like to make an appointment for a consultation with a physician Memorial Sloan Kettering to discuss your treatment options, you may call our Physician Referral Service at 800-525-2225.

Thank you for reaching out to us.

I was very interested in the discussion of basket trials for treating cancer at MSKCC. I learned from another web site that six basket trials are ongoing. Where can I learn more about these trials and whether I might be eligible? I have recurrent metastatic muscle-invasive bladder cancer with no genetic testing yet performed. Thank you so much.