Novel clinical trial designs match drugs to patient’s tumor profiles.
The Clearity Foundation
Cory Bentley, PhD
Bringing new treatments to ovarian cancer patients is very challenging. There are not as many patients diagnosed with this cancer as there are with other cancer types, such as breast, lung and colorectal, so there are not as many women who can enroll in clinical trials. Additionally, ovarian cancer patients are further divided into even smaller groups by the different types and great diversity of their tumors. The challenge of finding successful treatments is made more difficult by the fact that most ovarian cancers are not found until they are at advanced stages. All cancer patients, not just ovarian cancer patients, could benefit from effective drugs reaching the clinic more quickly and efficiently.
Scientists, clinicians, drug developers and academic institutions are starting to take on this challenge by changing the way new drugs are tested in cancer. They are using two new trial designs, adaptive trials and biomarker-guided trials often referred to as basket or bucket trials. The adaptive trial design allows researchers to make changes during the course of the trial based on results seen in earlier participants. This usually means that an interim analysis of the data suggested that patients with a particular tumor molecular profile may be benefiting from a given drug. Consequently, more patients with that profile are assigned to that drug as the trial enrolls new patients. In bucket or basket trials, patients are matched to drugs that research suggests will benefit them based on their personal tumor molecular profile.
The I-SPY 2 trial, which is ongoing, utilizes an adaptive trial design in breast cancer patients to evaluate up to 12 different drugs from several drug companies. Two drugs have so far emerged from this trial as promising additions to standard of care for patients with cancers that have specific molecular profiles: veliparib plus carboplatin for triple-negative breast cancer (ER, PR, and HER2-negative) and niratenib for HER2-positive hormone receptor-negative breast cancer. The identification of niratenib and veliparib/carboplatin as potential breast cancer treatments for these very defined subsets of breast cancer highlights several of the advantages of the adaptive trial design: first, more than one trial drug has been identified from a single study, and secondly, the trial drug is matched to a molecularly defined subset of patients most likely to benefit from the drug. Another advantage of the adaptive trial design is that patients are more likely to receive a trial drug since there is only one control group that receives the standard of care drug and multiple groups of patients who receive new trial drugs and combinations.
The planned NCI-MATCH trial is an example of a bucket/basket design. The MATCH trial will enroll cancer patients regardless of the type of cancer they have. Based on the molecular profile of their tumor, patients will be divided into multiple study groups or “buckets” that will receive up to 30 different trial drugs. Patient responses will be assessed within each separate arm as well as within the study as a whole. Bucket/basket trials create an easier path for the development of drugs for patients with rare cancers, as well as for less common cancers where there is substantial diversity in molecular tumor profiles, such as is found in ovarian cancer. There are not many patients with low-grade serous ovarian carcinoma (LGSOC), just a few percent of all ovarian cancers. A traditional trial for this group can be both costly and slow for drug developers, and delay the time it takes the drug to be evaluated. A bucket/basket trial creates the opportunity for these patients to efficiently find a drug and trial that is a good molecular match.
Results from the first basket trial to be run in ovarian cancer were presented by researchers from Princess Margaret Cancer Centre in Toronto at the recent annual meeting for the American Society of Clinical Oncology (ASCO). This trial performed tumor molecular profiling for 55 women with several less common histological subtypes of ovarian cancer – all in the same phase I study. The data suggested that one group of these patients, those with a mutation in the gene called KRAS, could benefit from MEK inhibition. KRAS and MEK are both components of the RAS-MAPK cell-signaling pathway that promotes tumor growth (click here for more info at Clearity’s website). The patients with KRAS mutations had better responses when treated with a matched drug (a MEK inhibitor called MEK162, which was given in combination with a drug targeting PI3K), than patients who received a drug that was not matched (physician’s choice drug).
It is important to note that the clinical testing of a different MEK inhibitor (selumetinib) in a traditionally designed phase II clinical trial in LGSOC patients did not find additional benefit from matching a MEK inhibitor to MAPK pathway mutations, but this study did find that 65% of the patients benefited from MEK inhibition (for more details, click here to visit Clearity’s website). Clearly, more research and trials will be needed to parse out the most effective and best-matched treatments for LGSOC patients and all ovarian cancer patients. Ideally, these trials will be small and efficient, with maximal benefit for the patients enrolling in the trials and lead to better treatments for ovarian cancer soon! For ongoing trials with MEK inhibitors, click here and select “MEK” in the Molecular Target dropdown menu.
Adaptive trials and basket/bucket trials can give ovarian cancer patients access to many new promising drugs. The design of these trials not only increases the opportunity to find treatments for rare cancer types, but helps patients find the best molecularly matched treatments. These trials are faster and smaller. Clinical trial design is at last starting to address some of the challenges in finding new treatments for ovarian cancer patients.
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