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Abstract
The poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patients with ovarian or breast cancer with or without BRCA1/2 mutations. Lurbinectedin is an ecteinascidin that generates DNA double-strand breaks. We hypothesized that the combination of olaparib and lurbinectedin maximizes the DNA damage increasing the efficacy. A 3 + 3 dose-escalation study examined olaparib tablets with lurbinectedin every 21 days. The purpose of this phase I study is to determine the dose-limiting toxicities (DLTs) of the combination, to investigate the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), efficacy, pharmacokinetics, in addition to genotyping and translational studies. In total, 20 patients with ovarian and endometrial cancers were included. The most common adverse events were asthenia, nausea, vomiting, constipation, abdominal pain, neutropenia, anemia. DLT grade 4 neutropenia was observed in two patients in dose level (DL) 5, DL4 was defined as the MTD, and the RP2D was lurbinectedin 1.5 mg/m2 + olaparib 250 mg twice a day (BID). Mutational analysis revealed a median of 2 mutations/case, 53% of patients with mutations in the homologous recombination (HR) pathway. None of the patients reached a complete or partial response; however, 60% of stable disease was achieved. In conclusion, olaparib in combination with lurbinectedin was well tolerated with a disease control rate of 60%. These results deserve further evaluation of the combination in a phase II trial.
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Details
1 Hospital Quironsalud Valencia, Oncogynecologic Department, Initia Oncology, Valencia, Spain
2 Vall D’Hebron Institute of Oncology (VHIO), Medical Oncology Department, Vall D’Hebron University Hospital, Barcelona, Spain (GRID:grid.411083.f) (ISNI:0000 0001 0675 8654)
3 Fundación Instituto Valenciano de Oncología (IVO), Department of Medical Oncology, Valencia, Spain (GRID:grid.418082.7) (ISNI:0000 0004 1771 144X)
4 Sunnybrook Health Sciences Centre, Department of Medical Oncology and Hematology, Odette Cancer Centre, Toronto, Canada (GRID:grid.413104.3) (ISNI:0000 0000 9743 1587)
5 FINCIVO (Fundación de Investigación Clínica del IVO), Clinical Trials Department, Valencia, Spain (GRID:grid.413104.3)
6 Fundación Instituto Valenciano de Oncología, Laboratory of Molecular Biology, Valencia, Spain (GRID:grid.418082.7) (ISNI:0000 0004 1771 144X); Príncipe Felipe Research Center (CIPF), IVO-CIPF Joint Research Unit of Cancer, Valencia, Spain (GRID:grid.418274.c) (ISNI:0000 0004 0399 600X)
7 Fundación Instituto Valenciano de Oncología, Laboratory of Molecular Biology, Valencia, Spain (GRID:grid.418082.7) (ISNI:0000 0004 1771 144X); Príncipe Felipe Research Center (CIPF), IVO-CIPF Joint Research Unit of Cancer, Valencia, Spain (GRID:grid.418274.c) (ISNI:0000 0004 0399 600X); Catholic University of Valencia ‘San Vicente Martir’, Department of Pathology, School of Medicine, Valencia, Spain (GRID:grid.440831.a) (ISNI:0000 0004 1804 6963)