Cancer Research UK Centre for Drug Development, London, United Kingdom
Han Hsi Wong , Claire Barton , Gary Acton , Robert McLeod , Rachel Darby-Dowman , Janette McQuillan , Helen Turner , Susan Wan , Zoe Backholer , Jane Peters , Sarah E. R. Halford
Background: Phase I oncology trials are crucial in cancer drug development and have evolved over the years. We examined the trends in trial characteristics, dose-limiting toxicities (DLTs) and efficacy, and questioned whether the concepts of DLT and maximum-tolerated dose (MTD) were still helpful. Methods: Cancer Research UK Centre for Drug Development (CRUK CDD) sponsors phase I trials across the UK. We reviewed our experience of adult trials between 1995 and 2013. Results: Forty-nine trials were divided into two groups based on the starting date for recruitment: 1995-2003 (24 trials, n = 603) and 2004-2013 (25 trials, n = 750). From 1995-2003 to 2004-2013, there was a shift towards studying biological and targeted agents. Patients in the later years tended to be older, had a greater disease burden and were more likely to have received prior treatment, although baseline haematology and biochemistry test results were no worse. The incidence of DLTs was similar in both year groups (10.1% vs 11.5%; risk of death 0.7% vs 0.3%). DLTs such as neuropathy, stomatitis and thrombocytopenia were less common in the later trials, while the frequency of elevated liver enzymes was greater. Non-classical DLTs also emerged in the later trials, including hypertension, hypophosphatemia, cardiac and ophthalmic toxicities. Of a total of 219 DLT events, only four fell outside the protocol-defined criteria for a DLT. The overall disease control rate increased from 27.9% in 1995-2003 to 36.0% in 2004-2013 (P = 0.0033) due to improved disease stabilisation, and there was a trend towards a lower rate of progressive disease as best response (51.0% vs 46.3%, P > 0.05). Objective response rates as high as 33.3% (radioimmunotherapy in lymphoma) were observed, and were both disease- and agent-dependent. Doses at or above the MTD were associated with response to cytotoxics and radioimmunotherapy but not to other targeted agents. Conclusions: CRUK CDD phase I oncology trials continue to provide clinical benefit to participants while minimising toxicities, and DLT remains a helpful concept. However, pharmacodynamic rather than MTD endpoints are becoming increasingly important in defining the dose for subsequent trials.
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