Working Group Evaluates Designing Clinical Trials in Biomarker and Targeted Therapy Era – AACC.org

Oncology-related clinical trials fail more often than trials focused on other diseases

Working Group Evaluates Designing Clinical Trials in Biomarker and Targeted Therapy Era – AACC.org.

Oncology-related clinical trials fail more often than trials focused on other diseases, often during phase III, when much time and money has already been devoted to the research. The “heterogeneity of cancer across and within a disease” is likely one of the reasons these trials fail, says a report from the National Comprehensive Cancer Network (NCCN) Working Group on Clinical Trial Design in the Era of Multiple Biomarkers and Targeted Therapies, which offers recommendations for improving the clinical trial process.

“Cancers that have historically been grouped together according to histologic attributes can now be categorized into even smaller subgroups, often with unique prognoses and responses to both standard and targeted treatments,” the report states. “The heterogeneity is not just among cancers in different patients but also between and within tumor sites in the same person.”

As experts have begun recognizing this heterogeneity, there has been a movement away from a one-size-fits-all approach to cancer therapeutics, which in turn has led to major advancements in cancer care. Using predictive biomarkers to individualize patient treatment is one such effort that has “revolutionized care in some cancer subtypes,” the report states. “The paradigm of one companion diagnostic, one drug, and one clinical trial may not represent the most efficient or effective use of resources in the current medical, scientific, and economic environment.”

One type of clinical trial the authors described uses Bayesian adaptive design, “meaning that the probabilities that the current patient’s tumor will benefit from each of the available experimental therapies are calculated and the patient’s therapy is assigned proportional to these probabilities,” the report states. “This predictive probability is then used to select incoming patients for the experimental treatment arms that are most likely to succeed, based on the patients’ biomarker signatures.”

Adaptive trial designs allow researchers to estimate the likelihood of treatment success when matching biomarker profiles with drugs, “thus fast-tracking therapies to be more easily tested in smaller, targeted phase III trials,” the report states. “Interim analysis and selection of a validated surrogated point (pCR) also allow the trial to reach initial conclusions more rapidly.” Multidrug trials that use one control arm for multiple experimental therapies is another way to be more efficient. “The fact that it is more likely for a patient to be assigned to a therapy, particularly a therapy that is statistically more likely to work with the individual biology of that patient’s tumor, could also increase patient satisfaction and lead to increased trial participation.”

Of particular note to laboratorians, the report recommends that researchers should also consider testing the technology itself and the allocation and use of necessary tissue samples for performing tests. The quality of the sample may be affected by collection methods, handling, fixation, and storage. It’s important to develop and adhere to standard operating procedures for tissue sampling, handling, and storage, and to establish guidelines for tissue suitability, including what acceptable levels are for non-neoplastic tissue in biopsy samples. The report also notes that DNA-based methods, including Sanger sequencing and MALDI-TOF, have low DNA requirements and are very reproducible, yet not sensitive enough for use with samples that have low tumor content.

The issues raised in the report show the need for a more “comprehensive, multiplexed molecular data for more patients at all stages of disease across tumor types,” the authors wrote. “Sequential testing for individual genetic aberrations quickly exhausts valuable specimens and does not contribute as much to the overall understanding of carcinogenesis, treatment responses, and the development of resistance.”

Going forward, regulatory agencies should be open to new approaches, and the clinical trial process should be streamlined to “allow the evaluation of multiple promising targeted strategies at once, as in Lung-MAP and the I-SPY2 trial, and to broaden the testing of novel strategies across tumor types that share predictive biomarkers, as is being developed in the MATCH protocol.”