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

Mark Yarchoan, Melinda C. Myzak, Burles A. Johnson, Ana D. De Jesus-Acosta, Dung T. Le, Elizabeth M. Jaffee, Nilofer S. Azad, Ross C. Donehower, Lei Zheng, Paul E. Oberstein, Robert L. Fine, Daniel A. Laheru, Michael Goggins

Research output: Contribution to journalArticle

Abstract

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/m2 on days 1 and 8 and cisplatin 25 mg/m2 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/m2 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.

Original languageEnglish (US)
Pages (from-to)44073-44081
Number of pages9
JournalOncotarget
Volume8
Issue number27
DOIs
StatePublished - 2017

Fingerprint

Mitomycin
Pancreatic Neoplasms
Cisplatin
Adenocarcinoma
Maximum Tolerated Dose
Myelodysplastic Syndromes
Drug-Related Side Effects and Adverse Reactions
Polymerization
Lymphopenia
Germ-Line Mutation
Neutropenia
Tablets
Anemia
Safety
Mutation

Keywords

  • BRCA2
  • Cisplatin
  • Irinotecan
  • Olaparib
  • Pancreatic cancer

ASJC Scopus subject areas

  • Oncology

Cite this

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 D.; 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.

In: Oncotarget, Vol. 8, No. 27, 2017, p. 44073-44081.

Research output: Contribution to journalArticle

Yarchoan, Mark; Myzak, Melinda C.; Johnson, Burles A.; De Jesus-Acosta, Ana D.; 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.

In: Oncotarget, Vol. 8, No. 27, 2017, p. 44073-44081.

Research output: Contribution to journalArticle

@article{dcece5c775a24aad9e9f9f841d6e8aa9,
title = "Olaparib in combination with irinotecan, cisplatin, and mitomycin c in patients with advanced pancreatic cancer",
abstract = "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/m2 on days 1 and 8 and cisplatin 25 mg/m2 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/m2 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.",
keywords = "BRCA2, Cisplatin, Irinotecan, Olaparib, Pancreatic cancer",
author = "Mark Yarchoan and Myzak, {Melinda C.} and Johnson, {Burles A.} and {De Jesus-Acosta}, {Ana D.} and Le, {Dung T.} and Jaffee, {Elizabeth M.} and Azad, {Nilofer S.} and Donehower, {Ross C.} and Lei Zheng and Oberstein, {Paul E.} and Fine, {Robert L.} and Laheru, {Daniel A.} and Michael Goggins",
year = "2017",
doi = "10.18632/oncotarget.17237",
volume = "8",
pages = "44073--44081",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "27",

}

TY - JOUR

T1 - Olaparib in combination with irinotecan, cisplatin, and mitomycin c in patients with advanced pancreatic cancer

AU - Yarchoan,Mark

AU - Myzak,Melinda C.

AU - Johnson,Burles A.

AU - De Jesus-Acosta,Ana D.

AU - Le,Dung T.

AU - Jaffee,Elizabeth M.

AU - Azad,Nilofer S.

AU - Donehower,Ross C.

AU - Zheng,Lei

AU - Oberstein,Paul E.

AU - Fine,Robert L.

AU - Laheru,Daniel A.

AU - Goggins,Michael

PY - 2017

Y1 - 2017

N2 - 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/m2 on days 1 and 8 and cisplatin 25 mg/m2 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/m2 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.

AB - 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/m2 on days 1 and 8 and cisplatin 25 mg/m2 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/m2 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.

KW - BRCA2

KW - Cisplatin

KW - Irinotecan

KW - Olaparib

KW - Pancreatic cancer

UR - http://www.scopus.com/inward/record.url?scp=85021809229&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021809229&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.17237

DO - 10.18632/oncotarget.17237

M3 - Article

VL - 8

SP - 44073

EP - 44081

JO - Oncotarget

T2 - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 27

ER -