Advances in the understanding of cancer biology have enabled researchers from academia and the pharmaceutical industry to develop new approaches to designing and conducting clinical trials. Among the new concepts and designs for clinical trials that have emerged in recent years are the adaptive, main protocol, and platform trials designs (329). These designs allow researchers to modify aspects of the trial design, if needed, by leveraging the accumulating data, thereby increasing the efficiency of the clinical research process. Main protocol, also known as master protocol design, and platform design streamline clinical development and allow the evaluation of multiple new agents by matching the right therapeutics with the right patients earlier, reducing the number of patients who need to be enrolled in the trial, and decreasing the length of time it takes for a new anticancer therapeutic to be tested and made available to patients. Master protocol can answer multiple clinical questions within a single trial (329). The emergence of this clinical trial design has largely been driven by accumulating knowledge of the genetic mutations that underpin cancer initiation and growth. As one example, I-SPY 2 is one of the longest-running clinical trials that uses a master protocol which provides the regulatory framework to study multiple treatments for breast cancer within a single study (330). The platform design of the I-SPY 2 trial allows new treatments to enter and leave the study with a greater efficiency than traditional clinical trials. The study has led to the FDA approval of several breast cancer treatments, including the molecularly targeted therapeutic neratinib (Nerlynx) (331). Basket trials are another example of genetic mutation–based master protocol design in clinical trials (see Figure 14, p. 73). These trials allow researchers to test one anticancer therapeutic on a group of patients who all have the same type of genetic mutation, regardless of the anatomic site of the original cancer. As one example, the combination of molecularly targeted therapeutics dabrafenib and trametinib was shown to work against an array of cancer types characterized by a specific genetic feature, or biomarker, called the BRAF V600E mutation, in two recent basket trials including the NCI MATCH study (see Sidebar 9, p. 37) (109). Based on the data from these trials, the combination treatment received FDA approval in June 2022 and is now benefiting many patients with cancer (1). Based on a recent analysis, the use of novel trial designs in clinical cancer research has more than tripled, worldwide, over the past decade (332). As our understanding of cancer biology continues to evolve and we uncover some of the most elusive questions in cancer medicine (see Cancer Development: Integrating Knowledge, p. 35) clinical trial designs will need to evolve as well. Additionally, the design and conduct of clinical cancer research need to keep pace with the new wave of technological advances. Novel designs that integrate emerging approaches such as comprehensive tumor profiling (e.g., of genome, transcriptome, proteome, microbiome, and metabolome, among others), artificial intelligence and machine learning, real-world evidence and data, and leverage inputs from patient advocacy communities and social media platforms will be pivotal to advancing the frontier of cancer clinical trials (333). Two of the most pressing challenges that need to be overcome urgently are low participation in cancer clinical trials and a lack of sociodemographic diversity among those who do participate (see Sidebar 28, p. 74). Low participation in clinical trials means that many trials fail to enroll enough participants to draw meaningful conclusions about the effectiveness of the anticancer therapeutic being tested. Lack of diversity in clinical studies means that the trial participant population does not What Is Medical Research? Medical research, sometimes referred to as biomedical research, as defined by the Organization for Economic Cooperation and Development (OECD), comprises: The study of specific diseases and conditions (mental or physical), including detection, cause, prevention, treatment, and rehabilitation of persons. The design of methods, drugs, and devices used to diagnose, support, and maintain the individual during and after treatment for specific diseases or conditions. The scientific investigation required to understand the underlying life processes that affect disease and human wellbeing, including areas such as the cellular and molecular bases of diseases, genetics, and immunology. Any individual whose work falls within the definition of medical research is part of the medical research community. Thus, the medical research community includes, but is not limited to, basic and translational researchers working in a wide range of disciplines, including biology, chemistry, immunology, physics, engineering, and computer science; physician-scientists; health care providers; and population scientists. Adapted from (163). SIDEBAR 25 Advancing the Frontiers of Cancer Science and Medicine AACR Cancer Progress Report 2023 69
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