35 The Drug Rediscovery Protocol ment-related adverse events (following the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03) of grade 3 or higher were documented. The response to the treatment was evaluated every 2 months (up to every 3 months for patients who remained in the study for ≥6 months), and classified by local investigators according to internationally accepted criteria for each tumour type29-33. The study treatment could continue until progressive disease (patients who were receiving immune-system-stimulating agents were permitted to continue treatment in case of pseudo-progression), unacceptable treatment-related toxicity, death, pregnancy, consent withdrawal or withdrawal from the study at the discretion of the investigator. BASELINE TUMOUR BIOPSIES A fresh, frozen tumour biopsy specimen was mandatory before treatment initiation (baseline biopsy had to be obtained ≤2 months before enrolment, and without any anticancer therapy within those ≤2 months), and was optional during and after study treatment. All biopsies were sent to the central sequencing institute of the CPCT (Hartwig Medical Foundation (HMF), Amsterdam, The Netherlands), together with a 10-ml blood sample to determine the background variation of the germline DNA of the patient. If the tumour-cell percentage was ≥ 30% and the DNA yield was ≥ 300 ng, WGS and biomarker analyses were performed. The WGS data and treatment details were stored in a national centralized database (at the HMF). In addition, a sequencing report was returned to the local principal investigator and could be used to re-assess eligibility if a patient progressed on initial study treatment. As the baseline biopsy was obtained after enrolment, the baseline WGS results did not affect the initiation of the study treatment. For each patient, a unique patient identification number was generated by the electronic case-report file system. This number was used by the study team and external researchers for data and sample collection and analysis, and could be tracked back to the individual patient only by the local sub-investigator. In addition to a summary of somatic variants across cancer-related genes, the sequencing report contained information regarding complex molecular features of the tumour, including the mutational load and microsatellite instability. The tumour mutational load represents the total number of somatic missense variants across the protein-coding region of the tumour genome. The microsatellite (in)stability score represents the number of somatic insertions and deletions in short repeat sections across the tumour genome per megabase. This metric can be considered as a good marker for instability in microsatellite repeat regions34, and has extensively been validated against the standard MSI–PCR assay used in routine practice (data not shown). COHORT DESIGN The study comprised multiple parallel cohorts, each defined by one histologic tumour type, one molecular tumour variant and one study treatment. For the purposes of cohort definition, the variant category was defined at the level of the gene or receptor that contains the 2
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