26 CHAPTER 2 ity and DNA-repair deficiency), the protocol allows for cohorts in which tumour types are combined. A Simon-like two-stage design is used per cohort15,16, in which 8 patients are enrolled in stage I and up to 24 patients are enrolled in stage II—provided that clinical benefit (which we define as complete or partial response, or stable disease beyond 16 weeks, measured 2-or-more times, ≥28 days apart) is observed at least once in stage I. A drug warrants further investigation in a particular cohort if ≥5 out of 24 patients experience a clinical benefit. If fewer responses are observed, the cohort is closed; results will be made public whether or not the cohort is successful. This design has 85% power to reject a rate of clinical benefit of 10%, if the true percentage is 30% (α error rate of 7.8%). The analysis of closed cohorts with some activity allows for the opening of new cohorts with refined criteria for inclusion. Figure 1. Study design. Schematic overview of the study and cohort design. For each study drug, a theoretically unlimited number of cohorts can be opened in parallel, depending on the tumour types and tumour profiles of submitted patients and the amount of the drug being studied that is available. A new cohort is opened for each combination of tumour type, tumour profile and study treatment. In each cohort, patients are enrolled in a two-stage design. Clinical benefit is defined as either complete or partial response, or absence of disease progression for ≥16 weeks, and must be measured 2 or more times and ≥28 days apart. Between September 2016 and September 2018, over 600 cases were submitted for central review and 294 patients started study treatment. Extended Data Figure 1 provides details of the review process, and Extended Data Figure 2 provides an overview of case submissions. To allow for sufficient follow-up (≥5 months for patients on study treatment), here we pres-
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