A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors
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 an...
Guardado en:
| Autores principales: | , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/d1515ed3222c482292aa0ffa3a73aad2 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:d1515ed3222c482292aa0ffa3a73aad2 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:d1515ed3222c482292aa0ffa3a73aad22021-12-02T13:20:22ZA phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors10.1038/s41598-021-82671-w2045-2322https://doaj.org/article/d1515ed3222c482292aa0ffa3a73aad22021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82671-whttps://doaj.org/toc/2045-2322Abstract 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.Andres PovedaAna OakninIgnacio RomeroAngel Guerrero-ZotanoLorena Fariñas-MadridVictor Rodriguez-FreixinosPedro MallolRaquel Lopez-ReigJose Antonio Lopez-GuerreroNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Andres Poveda Ana Oaknin Ignacio Romero Angel Guerrero-Zotano Lorena Fariñas-Madrid Victor Rodriguez-Freixinos Pedro Mallol Raquel Lopez-Reig Jose Antonio Lopez-Guerrero A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors |
| description |
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. |
| format |
article |
| author |
Andres Poveda Ana Oaknin Ignacio Romero Angel Guerrero-Zotano Lorena Fariñas-Madrid Victor Rodriguez-Freixinos Pedro Mallol Raquel Lopez-Reig Jose Antonio Lopez-Guerrero |
| author_facet |
Andres Poveda Ana Oaknin Ignacio Romero Angel Guerrero-Zotano Lorena Fariñas-Madrid Victor Rodriguez-Freixinos Pedro Mallol Raquel Lopez-Reig Jose Antonio Lopez-Guerrero |
| author_sort |
Andres Poveda |
| title |
A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors |
| title_short |
A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors |
| title_full |
A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors |
| title_fullStr |
A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors |
| title_full_unstemmed |
A phase I dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors |
| title_sort |
phase i dose-finding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/d1515ed3222c482292aa0ffa3a73aad2 |
| work_keys_str_mv |
AT andrespoveda aphaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT anaoaknin aphaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT ignacioromero aphaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT angelguerrerozotano aphaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT lorenafarinasmadrid aphaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT victorrodriguezfreixinos aphaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT pedromallol aphaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT raquellopezreig aphaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT joseantoniolopezguerrero aphaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT andrespoveda phaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT anaoaknin phaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT ignacioromero phaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT angelguerrerozotano phaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT lorenafarinasmadrid phaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT victorrodriguezfreixinos phaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT pedromallol phaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT raquellopezreig phaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors AT joseantoniolopezguerrero phaseidosefindingpharmacokineticsandgenotypingstudyofolaparibandlurbinectedininpatientswithadvancedsolidtumors |
| _version_ |
1718393240144576512 |