Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer

BACKGROUND: Olaparib is an oral inhibitor of polyadenosine 5’-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: In this phase 1 dose-escalation trial in patients with un...

Descripción completa

Detalles Bibliográficos
Autores principales: Yarchoan, Mark, Myzak, Melinda C., Johnson, Burles A., De Jesus-Acosta, Ana, Le, Dung T., Jaffee, Elizabeth M., Azad, Nilofer S., Donehower, Ross C., Zheng, Lei, Oberstein, Paul E., Fine, Robert L., Laheru, Daniel A., Goggins, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546463/
https://www.ncbi.nlm.nih.gov/pubmed/28454122
http://dx.doi.org/10.18632/oncotarget.17237
_version_ 1783255552565968896
author Yarchoan, Mark
Myzak, Melinda C.
Johnson, Burles A.
De Jesus-Acosta, Ana
Le, Dung T.
Jaffee, Elizabeth M.
Azad, Nilofer S.
Donehower, Ross C.
Zheng, Lei
Oberstein, Paul E.
Fine, Robert L.
Laheru, Daniel A.
Goggins, Michael
author_facet Yarchoan, Mark
Myzak, Melinda C.
Johnson, Burles A.
De Jesus-Acosta, Ana
Le, Dung T.
Jaffee, Elizabeth M.
Azad, Nilofer S.
Donehower, Ross C.
Zheng, Lei
Oberstein, Paul E.
Fine, Robert L.
Laheru, Daniel A.
Goggins, Michael
author_sort Yarchoan, Mark
collection PubMed
description BACKGROUND: Olaparib is an oral inhibitor of polyadenosine 5’-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: In this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m(2) on days 1 and 8 and cisplatin 25 mg/m(2) on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m(2) on day 1 to this regimen (olaparib plus ICM). RESULTS: 18 patients with unresectable PDAC were enrolled. The MTD of olaparib plus IC was olaparib 100 mg twice-daily on days 1 and 8. The addition of mitomycin C to this dose level was not tolerated. Grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities included neutropenia (89%), lymphopenia (72%), and anemia (22%). Two patients (11%), both of whom had remained on study for more than 12 cycles, developed drug-related myelodysplastic syndrome (MDS). The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years, but died from complications of treatment-related MDS. CONCLUSIONS: Olaparib had substantial toxicity when combined with IC or ICM in patients with PDAC, and this treatment combination did not have an acceptable risk/benefit profile for further study. However, durable clinical responses were observed in a subset of patients and further clinical investigation of PARP inhibitors in PDAC is warranted. TRIAL REGISTRATION: This clinical trial was registered on ClinicalTrials.gov as NCT01296763.
format Online
Article
Text
id pubmed-5546463
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-55464632017-08-23 Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer Yarchoan, Mark Myzak, Melinda C. Johnson, Burles A. De Jesus-Acosta, Ana Le, Dung T. Jaffee, Elizabeth M. Azad, Nilofer S. Donehower, Ross C. Zheng, Lei Oberstein, Paul E. Fine, Robert L. Laheru, Daniel A. Goggins, Michael Oncotarget Research Paper BACKGROUND: Olaparib is an oral inhibitor of polyadenosine 5’-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: In this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m(2) on days 1 and 8 and cisplatin 25 mg/m(2) on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m(2) on day 1 to this regimen (olaparib plus ICM). RESULTS: 18 patients with unresectable PDAC were enrolled. The MTD of olaparib plus IC was olaparib 100 mg twice-daily on days 1 and 8. The addition of mitomycin C to this dose level was not tolerated. Grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities included neutropenia (89%), lymphopenia (72%), and anemia (22%). Two patients (11%), both of whom had remained on study for more than 12 cycles, developed drug-related myelodysplastic syndrome (MDS). The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years, but died from complications of treatment-related MDS. CONCLUSIONS: Olaparib had substantial toxicity when combined with IC or ICM in patients with PDAC, and this treatment combination did not have an acceptable risk/benefit profile for further study. However, durable clinical responses were observed in a subset of patients and further clinical investigation of PARP inhibitors in PDAC is warranted. TRIAL REGISTRATION: This clinical trial was registered on ClinicalTrials.gov as NCT01296763. Impact Journals LLC 2017-04-19 /pmc/articles/PMC5546463/ /pubmed/28454122 http://dx.doi.org/10.18632/oncotarget.17237 Text en Copyright: © 2017 Yarchoan et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Yarchoan, Mark
Myzak, Melinda C.
Johnson, Burles A.
De Jesus-Acosta, Ana
Le, Dung T.
Jaffee, Elizabeth M.
Azad, Nilofer S.
Donehower, Ross C.
Zheng, Lei
Oberstein, Paul E.
Fine, Robert L.
Laheru, Daniel A.
Goggins, Michael
Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer
title Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer
title_full Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer
title_fullStr Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer
title_full_unstemmed Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer
title_short Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer
title_sort olaparib in combination with irinotecan, cisplatin, and mitomycin c in patients with advanced pancreatic cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546463/
https://www.ncbi.nlm.nih.gov/pubmed/28454122
http://dx.doi.org/10.18632/oncotarget.17237
work_keys_str_mv AT yarchoanmark olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT myzakmelindac olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT johnsonburlesa olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT dejesusacostaana olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT ledungt olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT jaffeeelizabethm olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT azadnilofers olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT donehowerrossc olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT zhenglei olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT obersteinpaule olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT finerobertl olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT laherudaniela olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer
AT gogginsmichael olaparibincombinationwithirinotecancisplatinandmitomycincinpatientswithadvancedpancreaticcancer