2026-04-13T05:41:47Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/59652024-12-13T11:00:42Zcom_2072_378070com_2072_378040col_2072_378092

A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors Poveda, Andres Oaknin Benzaquen, Ana Mazaltob Romero, Ignacio Guerrero‑Zotano, Angel Fariñas Madrid, Lorena Rodriguez‑Freixinos, Victor Institut Català de la Salut [Poveda A] Oncogynecologic Department, Initia Oncology, Hospital Quironsalud Valencia, Avda Blasco Ibañez, 14, 46 010 Valencia, Spain. [Oaknin A, Fariñas-Madrid L] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Romero I, Guerrero-Zotano A] Department of Medical Oncology, Fundación Instituto Valenciano de Oncología (IVO), Valencia, Spain. [Rodriguez-Freixinos V] Department of Medical Oncology and Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada Vall d'Hebron Barcelona Hospital Campus Medicaments antineoplàstics Càncer Medicaments - Eficàcia PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Dose-Response Relationship, Drug DISEASES::Neoplasms ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Therapeutics::Drug Therapy::Drug Therapy, Combination FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::relación dosis-respuesta de medicamentos ENFERMEDADES::neoplasias TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::terapéutica::farmacoterapia::farmacoterapia combinada Càncer; Biologia molecular; Oncologia Cancer; Molecular biology; Oncology Cáncer; Biología molecular; Oncología 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. This trial was sponsored by AstraZeneca and PharmaMar, including supply of study drugs. 2021-05-21T10:35:58Z 2021-05-21T10:35:58Z 2021-02-24 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Poveda A, Oaknin A, Romero I, Guerrero-Zotano A, Fariñas-Madrid L, Rodriguez-Freixinos V, et al. A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors. Sci Rep. 2021 Dec 24;11:4433. 2045-2322 https://hdl.handle.net/11351/5965 10.1038/s41598-021-82671-w 33627685 000626806200025 http://hdl.handle.net/11351/5965 eng Scientific Reports;11 https://doi.org/10.1038/s41598-021-82671-w Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf Nature Research Scientia