The number of regulatory approvals for oncology new molecular entities has risen rapidly over the past 5 years. This is likely due to our ability to design targeted agents, a consequence of our improved insight into the molecular basis of cancer. As a result, several new drugs have demonstrated exceptional clinical activity in small phase I or phase II trials. This has led to the increased use of regulatory mechanisms that allow initial approval on the basis of these early data and, more recently, the introduction of the breakthrough therapy designation (BTD) in the United States in 2012 and the anticipated piloting of Sakigake in Japan and PRIME in Europe in 2016 [1, 2].An analysis of oncology regulatory approvals since 2011 reveals that 'exceptional activity' in phase I or phase II trials strongly predicts sustained efficacy in subsequent phase III studies (Table 1). For our proposal, 'exceptional activity' is defined as (i) an objective response rate (ORR) of ≥50% to a single agent (with relevant response durability and some complete responses) or (ii) a hazard ratio (HR) of ≤0.5 in an early randomized study (Table 1). Examples of drugs that showed 'exceptional activity' in phase I or phase II trials include ceritinib, ibrutinib, and palbociclib, which received BTD and subsequent accelerated approval in the United States, and crizotinib, which was granted accelerated approval in the pre-BTD era. However, in spite of the 'exceptional activity' leading to accelerated approval, full regulatory approval was contingent upon subsequent verification of clinical benefit in confirmatory phase III randomized controlled trials (RCTs).Recently, there has been a growing interest in the systematic collection of real-world data to gain further insight into the impact of new drugs as they are introduced into clinical practice. This is exemplified by the new technology platforms CancerLinQ™ (by the American Society of Clinical Oncology) and Flatiron (by Flatiron Health, a health care information technology company). Furthermore, payers, physicians, and patients increasingly require more data on alternative comparators, specific subgroups, patient-reported outcomes, and long-term toxicities-data that may be more appropriately collected in real-world studies than in separate confirmatory trials.This reality raises a few questions:(i) When a drug demonstrates 'exceptional activity' and receives accelerated/conditional approval and/or BTD, are
These findings indicate that RSR13 in combination with oxygen breathing does not alter the cytotoxicity of cisplatin or carboplatin when used simultaneously, as a pretreatment or as a posttreatment in vitro or in vivo. Our in vivo findings indicate trends that support previous findings that cisplatin is more cytotoxic to well-oxygenated tumor cells than to hypoxic tumor cells, and that this effect can be improved by improving tumor oxygenation, but the differences seen in our studies did not achieve statistical significance.
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