Two years ago, Richard L. Schilsky, MD, FACP, FASCO, Chief Medical Officer of ASCO, proposed a unique clinical trial concept during an educational session on the challenges of delivering precision medicine services in a community setting at ASCO’s Annual Meeting. The idea was to design a clinical study that would serve two purposes: match commercially available targeted therapies to the genomic profile of patients’ tumors to determine the activity of the drugs when used off label and simplify patients’ access to the drugs, providing patients with truly personalized cancer care. After presenting the concept to ASCO’s Cancer Research Committee, Dr. Schilsky received approval and funding from ASCO to proceed with the development of the Targeted Agent and Profiling Utilization Registry (TAPUR) study, a prospective, nonrandomized clinical trial, which is slated to launch at the beginning of 2016.
The main objective of TAPUR is to collect information on the antitumor activity and toxicity of commercially available, targeted cancer therapies for advanced solid tumors and for two types of blood cancer, multiple myeloma and B-cell non-Hodgkin lymphoma. Patients who are no longer benefitting from standard treatment, are healthy enough to participate in the study, and have a genomic variation in the tumor that can be targeted with a study drug are eligible to enroll in TAPUR. Currently, five pharmaceutical companies—AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, and Pfizer—are contributing drugs to the TAPUR trial, and ASCO is in discussions with other pharmaceutical companies interested in participating, according to Dr. Schilsky.
To ensure that TAPUR follows the best clinical trial practices, ASCO has established three oversight committees: a Steering Committee to oversee study operations; a Molecular Tumor Board to review the proposed drug-target match; and a Data and Safety Monitoring Board to review study results, monitor for unexpected adverse events, and determine when to release data.
The ASCO Post talked with Dr. Schilsky, who is the principal investigator of TAPUR, about ASCO’s decision to launch its first-ever clinical investigation and how it will advance precision medicine in cancer care.
Trial Objectives
Why did ASCO decide to launch TAPUR?
We recognized that we have an opportunity to learn in a scientific setting what we are increasingly seeing in oncology practice in this era of genomic profiling. Patients with advanced cancer who have no other treatment options see the potential of getting a genomic profile of their tumor, which could possibly reveal an abnormality in the cancer that could be targeted with a drug that they otherwise might never have received or their doctor might never have thought about trying.
Genomic profiling is happening more and more frequently because the testing is more widely available, and there are many targeted drugs that are already approved by the U.S. Food and Drug Administration (FDA) and available for off-label prescribing. The problem is that patients often can’t get access to these drugs or reimbursed for them because they are being used off-label and there is no proof of benefit. Most importantly, even if patients do get access to the treatment, nobody outside of the patients’ medical teams ever learn what the patients’ outcomes are or whether this is a worthwhile strategy.
TAPUR is a focused effort to learn from real-world clinical practice in a very well delineated area. You can almost think of TAPUR as a microcosm of what we hope to accomplish with CancerLinQ™, the Society’s health information technology platform. CancerLinQ will allow us to learn about all the dimensions of real-world clinical practice, and TAPUR will allow us to learn about this very specific dimension of clinical practice: the off-label prescribing of targeted drugs.
We feel that the timing is right to capture this information, and it is central to ASCO’s view that we can learn from observing real-world clinical practice. TAPUR will also provide opportunities and mechanisms to help oncologists, particularly in the community setting, to learn more about how to utilize genomic testing in their practices and how to prescribe targeted therapies.
By having a research protocol that provides guidance to doctors on how to match drugs to gene mutations, we will be able to achieve a certain educational function as well as the research objectives of the study. And in the long run, that may be among the most valuable assets we provide oncologists who are not working in the major academic medical centers, so their patients can benefit from these precision medicine approaches.
Hematologic Targets
The cancer types in TAPUR include advanced solid tumors, multiple myeloma, and B-cell non-Hodgkin lymphoma. Why did you choose those two blood cancers?
We choose those two because they are the most common blood cancers that occur in adults, and there are already targeted therapies for them that have shown effectiveness. And we are beginning to see some crossover effects, meaning that some targeted therapies that are effective in solid tumors are also showing effectiveness in some of these blood cancers, so we thought that we would be likely to get a sufficient number of patients with myeloma or non-Hodgkin lymphoma and a sufficient number of drug matches to learn something.
Study Design
What is the endpoint and duration of the study?
Right now, the study is set for a 3-year duration. We think that by the end of 3 years, we will learn whether TAPUR can generate useful information. If it does, then we hope to continue it beyond that 3-year point.
The endpoint is to find persuasive evidence that these targeted drugs prescribed off-label are or are not active in particular tumor types with particular genomic variations. This is a type of investigation that is often called a signal-finding or hypothesis-generating study. We are not trying to prove anything in a definitive way, but we are trying to get a sense of whether a targeted drug used off-label in a specific patient population is sufficiently active to warrant further study of that drug in that patient population.
Improved Care
How will this study advance precision medicine in oncology care?
We hope it will advance precision medicine in a number of ways. First and foremost, we hope it will generate important signals of drug activity or signals that suggest using a drug in a particular population might not be useful. Both of those would be important to know because if we find a new signal of activity, then there is an opportunity for the drug manufacturer or other researchers to pursue that further and maybe develop the drug in a new indication, which would give new treatment options to patients. If we don’t find any activity of a drug in a certain population, we would want to discourage the off-label prescribing of that drug and encourage patients to go on clinical trials or find other kinds of treatment options.
In a broader sense, we hope TAPUR will give us a much better understanding of how to interpret clinical genomic tests at the point of care and the best way to use that information to guide a doctor and patient to a particular therapeutic approach. Hopefully, we will also learn about the effectiveness of a molecular tumor board, which we will conduct in conjunction with TAPUR. We will be able to report on how it operates and how often it recommends a treatment approach that is different from what the treating physician is proposing.
Finally, I think we will learn a lot about the infrastructure necessary for precision medicine care and research to inform further advancement of the whole field.
Anticipated Time Line
When do you expect to have some early results from TAPUR?
It depends on the frequency of the genomic abnormalities we see in the patients enrolled in the study. If we see fairly common abnormalities and can enroll patients into the various cohorts pretty quickly, I think we will be able to generate some useful information within the first year. If all of the variations we see are very rare, then it’s going to take more time to fill those cohorts with a sufficient number of patients to do an analysis of the study.
Our hope is that prior to the 3-year mark, we will be able to assess whether we are generating useful information often enough to justify continuing TAPUR or whether it needs to be modified in some way. Or we might conclude that TAPUR is not the right approach to gathering this information and that we should do something different.
Future Study Design
Is TAPUR an example of how clinical studies will be designed in the future?
There is no doubt about that. We are already seeing that this design is the only way to proceed in order to obtain some kinds of information. The real struggle going forward will be in understanding the full complexity of a patient’s tumor. TAPUR is designed to match a drug to an abnormality in the cancer genome based upon a single abnormality—a specific mutation in a single gene. We know that the cancer genome is much more complicated than that, so we have to figure out how to design studies that allow us to match a drug to a genetic signature that we determine based on an analysis of multiple genes in the tumor specimen or in multiple pathways that are activated due to those genetic abnormalities.
Of course, the problem is not just in gene mutations. The cancer can be driven by genetic amplification, the translocation of genes, or the epigenetic modification of genes that can activate a pathway. Biologists will say it is not all just in the genome, because the genome only provides the basic information that operates the molecular pathways inside the cell, and it is the pathways that actually produce the malignant phenotype.
We will need to get even more sophisticated in our thinking about how to ascertain pathway activation and use that information as a basis for drug matching. We are continuously peeling the cancer onion, and every time we do, we find out how much more complex the situation is than we initially thought. But we will eventually get to the place where we have the right pieces of information to optimize treatment for each patient.
Study Expansion Plans
Currently, TAPUR is being launched in just two states, Michigan and North Carolina. Do you have plans to expand the study to other states?
Yes. Initially, we are expecting to offer TAPUR in about 40 sites throughout Michigan and North Carolina. We have limited it to two states primarily to ensure that we have constructed TAPUR properly and that it functions the way we need it to function, because this is ASCO’s first clinical trial, and we need to have our infrastructure right.
As quickly as possible after the launch, we plan to expand the study to other states, and we are already accepting statements of interest from other sites. Any center interested in participating in the TAPUR study should e-mail us at TAPUR@asco.org.
For more information about the TAPUR study, see "TAPUR: ASCO’s First Clinical Trial Addresses Critical Gaps in Understanding of and Access to Targeted Therapies" or visit www.tapur.org; for questions, e-mail TAPUR@asco.org.■
