Procedures
toxicity, toxicities, death, tumour
TUMOUR, APPENDIX
In the Phase 1 dose escalation, participants received escalating doses of olaparib twice daily with ramucirumab 8 mg/kg on day 1 in 14-day cycles. Two dose levels of olaparib 200 (dose level 1) and 300 mg twice daily (dose level 2) were evaluated in a 3 + 3 design. In the Phase 2 dose expansion, participants received the RP2D of olaparib with the standard dose of ramucirumab at 8 mg/kg every 14 days. Dose modifications were allowed to manage clinically significant toxicities as specified in the protocol. Participants received study treatment until radiographic or symptomatic progression, unacceptable toxicity, death, or withdrawal from the study. Radiographic tumour assessments were performed at baseline and every 6 weeks for the duration of the study.Molecular profiling was performed on formalin-fixed paraffin-embedded tissue from pre-treatment biopsies by whole exome sequencing (WES) and targeted sequencing with the BROCA-HR panel. An on-treatment biopsy was changed from mandatory to optional in a protocol amendment prior to any patients enrolling to facilitate enrollment. The WES was performed on the Ion Torrent sequencing platform, utilising IonAmpliSeq Exome RDY library kits with 60 ng of genomic tumour DNA extracted from formalin-fixed paraffin-embedded tissue sections and normal tissue from the same patient. Templating of libraries on chips was carried out using an Ion CHEF instrument and sequencing done on an S5XL instrument, followed by analysis with Torrent Suite software. The BROCA-HR panel was run on normal and tumour tissue using the Illumina platform covering 73 genes including clinically relevant HRD genes, and was performed at the University of Washington (a full list of the BROCA-HR panel is available in the Appendix). As pre-specified in the protocol a tumour was considered to have HRD if an inherited or somatic pathogenic variant was present in any of the following 17 HRD genes and non-HRD in the absence of these mutations: 