As technology and science have evolved over the last several years, new treatment modalities for cancer have emerged. These new treatment options have presented a challenge for researchers. How do we translate new scientific advancements to patient populations rapidly and effectively, especially in oncology? Arguments that the drug development process is “broken” have stimulated improvements in clinical trial designs.1 One category of clinical trial design that has emerged as a result is a master protocol. Several designs fall under the master protocol category.
Master protocols are developed with a centralized protocol, with many arms that are specific to a disease process or population. Using the central protocol and specific criteria, each arm is its own study.2 This design allows for arms to be removed from the master protocol if an arm fails to show success or as new information becomes available.3 These new protocol designs use precision, or personalized, medicine to generate hypothesis for the study. The development of a study “arm” uses multiple new methodologies. Targeted therapy is able to determine a drug or combination of therapies that will eliminate the cancer cells while sparing the healthy and normal cells. Using this type of treatment can affect the ability of cancer cells to grow and recruit cells, or it can aid the immune system in fighting the cancer cells. Molecular profiling allows the physician to learn the precise genetic makeup of a tumor. Once the main issue of the DNA is determined, a targeted therapy can be identified, which may provide the best chance of fighting the cancer. Genomic profiling is more focused on the entire genome, as well as how the genes interact within a person or a specific cell and how this is affected by the environment. This method looks at many options for causes of the cancer and how to go about treating it.4 There are currently two generally recognized types of master protocol designs: umbrella trials and basket trials. They are similar, but still represent different methods of research. Umbrella trials normally are focused on a specific type or general class of cancer.5 Subjects with this one type of cancer are biopsied to find the genetic makeup of their tumor. They then are assigned, or randomized, into a treatment arm based on the prevalent genetic alteration.5 One of the arms in an umbrella trial usually is reserved for those patients who do not have a match to any of the specifically studied mutations.6 So the treatment arms are under the umbrella of the master protocol of a single type or category of cancer.
Basket trials are more complex. These trials have the master protocol, but the trial is looking at multiple mutations and the targeted treatment for each, usually with no interest in the organ origination of the cancer. Figure 1, adapted from the Birt-Hogg-Dube Syndrome Research blog, depicts this description of a basket trial in a visual form.7 Each genetic mutation or deficiency is one arm, with a specific drug therapy being tested.5 When designing a basket trial, randomization is not a commonly used tool. Because each basket is related to a genetic mutation and not a specific tumor type, there would be a different standard of care for each type of tumor. Basket trials are “…predicated on the hypothesis that the presence of a molecular marker predicts response to a targeted therapy independent of tumor histology” (p.975).2 Each arm, or genetic mutation, is its own protocol, and is a basket for multiple tumor types with the mutation in common.8 For instance, the genetic mutation may exist in several types of cancer, such as breast, colon, pancreatic, or other cancers.
Traditionally, treatment trials in oncology are used to obtain FDA approval for a new drug, and consist of Phase I, II, and III trials prior to FDA approval. After approval is achieved, Phase IV is used to continue to chart the safety of the drug, along with any new risks or benefits. There are also hundreds to thousands of participants involved in these treatment trials.9 In such traditional clinical trials, a new drug or combination of drugs is compared to the traditional standard of care for a particular cancer type. However, in this approach there are large numbers of subjects needed for statistically significant results, and often there is a small number of patients whose cancer is healed, and a small number with no effect or even disease progression.6 Using the above traditional clinical trial design, developing FDA-approved treatments is a lengthy and expensive endeavor. Moreover, if results are mixed, FDA approval is ultimately near impossible. The 12-year approval timeline (not to mention costs) delays needed treatments for diseases that have high mortality rates. Additionally, approval for one type of cancer at a time is another system of delays.9 Indeed, in the last 50 years, the cancer death rates have had minimal change, only declining 8%, despite life expectancy increasing by 30 years over the last 100 years.10 New advances in cancer treatment often are approved too late to effectively decrease mortality rates.
Basket trials, however, may be able to streamline the process of drug approval, and hopefully provide treatment advances at a more rapid pace. For basket trials to be successful and produce data that are significant, a collaboration of entities must be achieved.11 First, multiple treatment centers must be involved in screening and treatment of the patients. The development of assays to test the genetic structure of the tumors must be streamlined and validated for each site that is conducting the genetic testing. If there is a central testing site (or a few), shipping methods must be decided upon. While each site may require local institutional review board (IRB) approval of a protocol, multisite IRBs and/or centralized IRBs can oversee approvals, safety, and human subject protections. Lastly, pharmaceutical companies must be willing to collaborate with each other, academia, and governmental entities. The multiple arm design allows for multiple drugs to be tested simultaneously. The likelihood of all the involved drugs originating from one company is small, so involved companies must be dedicated to transparency and share in the costs and the benefits of these multi-armed trials.11
Personalized medicine in cancer
Researchers have found that although cancer is categorized by organ type, each person’s cancer is not exactly genetically identical. So, the treatment for Patient A’s melanoma may have no effect on Patient B’s melanoma, and vice versa. Research into the genetics of the cancerous tumor is evolving rapidly, and has been aided by the development of next-generation sequencing (NGS). NGS can examine a large amount DNA at one time.12 Four common approaches to DNA sequencing are the most prevalent NGS techniques. The first is whole-genome sequencing, which will sequence the entire genome of the sample. The whole-exome sequencing only identifies the protein-coding genes. Targeted exome sequencing tries to identify genes of interest, which allows sequencing with greater detail and precision. Lastly, “hotspot” sequencing allows specific regions of chosen genes, areas with frequently occurring mutations, to be the focus of the sequencing. The negative to this type of sequencing is that important mutations can be missed when only small areas are targeted. However, hotspot sequencing can offer a quicker output of results because of the targeted nature of the testing, and it is becoming a widely used and accepted NGS test for determining treatments.12 Evolution in cancer care is directly related to new developments in genetic testing and the discoveries of how certain mutations affect the body. A move toward precision medicine allows practitioners to focus on how the treatments can be tailored to each patient.3 The development of NGS sequencing technology reveals specific tumor genetics and growth mechanisms.13 This science reveals patterns of molecular changes between tumor types. However, this large amount of information gathered is unhelpful if it is not sorted and categorized. Therefore, databases being developed to categorize the discoveries, such as The Cancer Genome Atlas (TCGA). This database helps researchers identify patterns and determine which genes are the driver genes, providing a target for therapies being developed.12 Scientists are focusing attention on two basic cancer genes: driver genes and passenger genes. Driver genes, as the name implies, helps to “drive” the growth of the cancer cells and tumors. The driver gene has allowed a “growth advantage” to be provided for the cancer cells in the individual tissues. Passenger genes, however, obtain their mutations when the driver genes change; they do not “drive” the growth.13
However, the identification of driver genes is just the tip of the iceberg in what makes up a cancerous tumor. Finding the driver gene is an important first step in determining how to treat a patient. This is the mechanism that targeted therapy aims to influence or eliminate. If researchers can find a drug compound or combination of drugs that can alter how a driver gene operates and grows a tumor, there is potential for the treatment to stop and possibly reverse the growth of the cancer. Targeted therapy may be the new direction of cancer treatments.12
Immunotherapy is another recently developed cancer treatment being heavily studied. Immunotherapy uses the body’s own mechanisms of fighting foreign invaders to fight off cancer cells. These therapies can enhance the subject’s current immune system by affecting cancer cell growth or by helping the normal immune cells to better attack the cancer. Scientists are able to create these immune system cells in the lab, allowing them to produce the therapy for widespread use.14 While successful in some patients, many of these therapies may be even more effective when combined with an additional therapy, such as a therapy targeted for the genetics of the individual tumor.15
Advantages and disadvantages of basket trials
Basket trials offer distinct advantages in this new era of cancer treatment. (See Table 1.) With this trial design, researchers are able to identify responses in a smaller number of patients. With the success of a treatment arm, which is often designed as a Phase I trial, a larger trial can be opened to prove that it can be beneficial to many patients. As treatments are successful or fail, arms can be added or removed from the Master Protocol to better suit the research. By testing multiple treatments and abnormalities at the same time, drug approval timelines can be reduced.16 Because of the large number of subjects screened for the Master Protocol, basket trials lend themselves to developing genetic screening improvements and efficiency. The development of the assays to find the genetic issues in a tumor can provide detection for multiple biomarkers, including genetic mutations.17 Lastly, using the basket trial design can allow rare cancer types to be treated and studied. Because the criteria for the trial is not based on tumor location, these rare cancers may have one of the genetic mutations being studied. Being able to identify responses with only a small number of patients may allow a treatment to be determined for a rare cancer.18 Despite these advantages, there are also disadvantages to running a basket trial. Currently, basket trial designs rely on the hypothesis that tumors can be treated based on biomarkers (not necessarily on the origin of the tumor). In one of the first published papers using a basket trial design, the authors stated: “…analyses of genomic alterations in multiple tumor types have led to the following two fundamental observations: tumors originating in the same organ or tissue are genetically heterogeneous, and similar patterns of genomic alterations may be observed in tumors from different tissues of origin”(p.1000).19 More research needs to be done to determine if treatments can be based off genetics alone, or if the organ of origin will also affect the treatment outcome. The data used to determine the arms of the basket trial must be sound, relying on extensive preclinical work for genetic abnormalities, treatments for these alterations, and the basic science of tumor environments.16 Assays also need to be well-developed and trustworthy.6 Statistically, basket trials are difficult to assess. Because there are often so few subjects in an arm, are the results significant? The master protocol design may require that the achieved effect of each treatment arm is high to project successful outcomes for a majority of patients.
Inside a basket trial
When searching “basket trial” on ClinicalTrials.gov, a total of 38 studies are found. One of the largest basket trials currently recruiting patients is the trial titled “NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma” (NCT02465060).20 The official title of the trial is Molecular Analysis for Therapy Choice (MATCH). The MATCH trial is focusing on solid tumor and lymphoma cancers carrying various genetic abnormalities. These patients already have been treated with at least one standard of care treatment, and/or there is no other current standard treatment to offer them. With the discovery of targeted therapies, this trial is able to focus treatment directly to the mechanisms of the tumor or cancer. The trial is sponsored by the National Cancer Institute (NCI) and is enrolling at more than 1120 locations in the United States and Puerto Rico.21 The merger of the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network, now known as ECOG-ACRIN, is responsible for coordinating the trial and compiling the data.
MATCH is a Phase II trial, opened on August 12, 2015, with the primary objective being the evaluation of the number of subjects with an “objective response (OR)” to the targeted treatment on one of the 24 arms currently available (as of March 18, 2017).20 The trial has several other goals:
When joining the MATCH trial, patients start at Step 0. This step not only requires screening tests, such as imaging, blood draws, and electrocardiograms (ECGs), but the patient also must agree to undergo a biopsy, or have available frozen tissue that they are willing to provide for genetic testing. Once the biopsy tissue is collected, the material is shipped to the ECOG-ACRIN Central Biorepository and Pathology Facility, a central testing site located at MD Anderson Cancer Center. The processing time for each biopsy is approximately 14 days. If the patient has minimal tumor tissue in the first sample, a second biopsy can be performed. If an actionable mutation of interest (aMOI) is discovered, the patient will be assigned to a treatment arm, and re-consented to this specific portion of the protocol. At this point, treatment can start.22 If the patient progresses on the targeted therapy or is adversely affected by the treatment, other choices are available. The original biopsy results can be reviewed and a secondary aMOI could be presented as a potential treatment target. The patient also could restart the process with another biopsy. This process can be repeated up to a total of seven steps, as long as the progression is less than 6 months after treatment. The last step, if the patient consents, is a biopsy and blood collection at the end of the trial. This will be used for future research and to look for any clues to the resistance to treatments provided. The trial is open to men and women who are at least 18 years of age.20
The MATCH trial is considered unique for several reasons. First, it is the largest targeted therapy trial to date. The trial plans to screen 6000 patients, resulting in 3000 enrolled patients.21 There are currently 24 treatment arms with 17 different drugs/biologics and combinations of these to treat 24 different aMOIs that have been identified as trouble makers in multiple cancers. Because the MATCH trial does not focus on one cancer type as a traditional trial would, the treatment options can cover many types of cancer. While this is an interventional trial, each arm of the study is not competing against each other. The study is focusing on the performance of each drug on its own. Because the cancer type is not the focus, several rare diseases can be represented in the trial. These rare cancers could have the same genetic issues as more common cancer types.
One of the highlights of the MATCH trial is the collaboration of multiple specialists, researchers, and physicians in academia, government agencies, and pharmaceutical companies. This collaboration may be the future of scientific findings. In the 2016 State of the Union address, then President Barack Obama presented the Cancer Moonshot initiative. This initiative, headed by former Vice President Joe Biden, was created to help propel cancer research and discoveries at a quicker pace.23 The goal of Moonshot is to produce discoveries in 5 years that normally would take 10 years to develop. It is a lofty goal, and one that requires collaboration such as that found in the MATCH trial. Many different entities are coming together to provide knowledge, products, and assistance to each other for the greater good of cancer research. Precision medicine is one area that the Moonshot group believes can have a significant impact on future cancer research. The MATCH trial encompasses many of the goals of the Cancer Moonshot initiative.
Implications for clinical research personnel and physicians
The entire clinical research team is affected by this new “out of the box” clinical trial design. There are currently more than 1000 sites accruing patients to the MATCH trial including the OSU Wexner Medical Center-James Cancer Hospital at The Ohio State University. From patients to physicians, the overall enthusiasm about the MATCH trial is positive. An informal questionnaire was sent to 15 individuals involved in the MATCH trial. When asked about the challenges encountered from the implementation of the MATCH trial, the most prominent challenge was communication. Because the trial encompasses so many cancer specialties, trial personnel would include clinical research coordinators, data managers, lab and tissue collection personnel, along with physicians and their staff. With this number of trial staff, it is difficult to coordinate schedules for meetings, disseminate information, and ensure all steps of the study are progressing correctly. The sponsors (NCI and ECOG-ACRIN) change and update the protocol often, removing arms and adding new arms and treatments, therefore, communicating updates can be challenging. Additionally, the research staff reported that physicians’ interest in MATCH has become subdued. Often, the treatment options offered by MATCH are the last option for patients. The turnaround time for testing to treatment arm assignment or screen fail has been lengthy, taking up to 4-6 weeks in some cases. Patients cannot always delay treatment for this period of time. The sponsors have taken this into consideration and allowed other treatments during the wait time, but there are additional criteria for clearance to then start treatment on MATCH. Also, very few patients have been found to have the desired genetic alterations. According to an update by James H. Doroshow (NCI), tumor samples from 4702 subjects have been submitted as of 3/12/17. Of those patients, 722 had an aMOI, and 495 patients had enrolled in treatment.24 From a data perspective, the screening alone for the MATCH trial requires imaging, lab work, ECG, original diagnosis pathology, local pathology, tissue shipment, and receiving paperwork, as well as the required informed consent forms. There is a large amount of input required up front for patients who may never continue on in the study.
Despite the challenges, the majority of research practitioners see basket trials as advantageous for the patients and for scientific progress. The ability of this trial design to look at multiple diseases and treatments during the same timeline of a traditional trial will allow for more efficient use of resources and quicker, yet still safe, drug approvals. The ability to genetically screen so many patients, regardless of whether they are able to proceed in the MATCH trial, can help propel scientific knowledge. The tumor makeup can be studied, looking at all genetic issues involved, including the development of treatment resistance. The ability to have this amount of study tissue will be invaluable in future research into targeted therapy. The requirement of imaging, blood work, and other testing information can only improve what we can learn from the tissue testing.
In April 2016, the interim analysis of the MATCH trial was presented to a gathering of the American Association for Cancer Research. The original goal of the study was to screen 50 patients per month, but the initial enrollment was 795 patients in the first 3 months, exceeding expectations. The interim analysis affirmed that a trial focused on genetic abnormalities and not just one type of cancer is achievable. The team was able to derive genetic results from 87% of the tumor material that was submitted. This analysis also provided rationale for moving the trial from the original 10 treatment arms to 24 treatment arms, thus expanding research to additional genetic abnormalities and some very rare cancers.25
Basket trials in oncology have provided an alternative pathway to new drug approvals in the era of personalized medicine. Cancer may not be the only disease that can benefit from alternative trial design. Diseases having genetic components may also benefit from this trial design. There is certainly a new horizon for this alternative, yet complex trial design. Educating research practitioners on core competencies in clinical research, including an understanding of genomics, in addition to an emphasis on team science and communication, will prepare sites to meet this new challenge.
By Shannon R. Balser, MACPR, RVT, ALAT, and Carolynn T. Jones, DNP, MSPH, RN
This article was reprinted from Research Practitioner, Volume 18, Number 3, May-June 2017. Subscribe >>