Evolution of early phase clinical trials in oncology

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 96; no. 1; pp. 31 - 38
• Main Authors: Bui, Nam Q., Kummar, Shivaani
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 2018; Springer Nature B.V
• Subjects: Biomedical and Life Sciences; Biomedicine; Cancer; Cancer immunotherapy; Clinical trials; Drug development; Human Genetics; Internal Medicine; Molecular Medicine; Monoclonal antibodies; Oncology; Review; Targeted cancer therapy; Basket trials; Drug development; Umbrella trials; Phase 1 trials
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-017-1612-7

The therapeutic armamentarium for the treatment of cancer has rapidly evolved with the advent of molecularly targeted and immuno-oncology agents. Dramatic and prolonged responses observed in patients with advanced cancers have created excitement and promise for expedited development of effective new treatments. However, this has also necessitated a rethinking of our early phase clinical trial designs and the process of optimally developing a novel agent. In this review, we discuss the current state and future directions of phase I clinical trials in oncology. Firstly, we cover the statistical methodologies behind rules and model-based dose escalation designs, and what the future holds for optimal dose selection beyond targeting the maximum tolerated dose. Next, we discuss the recent adoption of seamless expansion strategies to expedite drug development timelines, highlighted by the pembrolizumab KEYNOTE-001 trial, and potential pitfalls with this approach. Finally, we delve into the concepts behind genomic matching trials, including early success stories and the challenges that lie ahead.