PMID- 28454122
OWN - NLM
STAT- MEDLINE
DCOM- 20180329
LR  - 20220330
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 8
IP  - 27
DP  - 2017 Jul 4
TI  - Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients 
      with advanced pancreatic cancer.
PG  - 44073-44081
LID - 10.18632/oncotarget.17237 [doi]
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. TRIAL REGISTRATION: This 
      clinical trial was registered on ClinicalTrials.gov as NCT01296763.
FAU - Yarchoan, Mark
AU  - Yarchoan M
AD  - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 
      USA.
FAU - Myzak, Melinda C
AU  - Myzak MC
AD  - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 
      USA.
FAU - Johnson, Burles A 3rd
AU  - Johnson BA 3rd
AD  - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 
      USA.
FAU - De Jesus-Acosta, Ana
AU  - De Jesus-Acosta A
AD  - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 
      USA.
FAU - Le, Dung T
AU  - Le DT
AD  - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 
      USA.
FAU - Jaffee, Elizabeth M
AU  - Jaffee EM
AD  - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 
      USA.
FAU - Azad, Nilofer S
AU  - Azad NS
AD  - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 
      USA.
FAU - Donehower, Ross C
AU  - Donehower RC
AD  - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 
      USA.
FAU - Zheng, Lei
AU  - Zheng L
AD  - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 
      USA.
FAU - Oberstein, Paul E
AU  - Oberstein PE
AD  - Columbia University Medical Center, New York, NY, USA.
FAU - Fine, Robert L
AU  - Fine RL
AD  - Columbia University Medical Center, New York, NY, USA.
FAU - Laheru, Daniel A
AU  - Laheru DA
AD  - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 
      USA.
FAU - Goggins, Michael
AU  - Goggins M
AD  - The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 
      USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01296763
GR  - R01 CA197296/CA/NCI NIH HHS/United States
GR  - RC2 CA148346/CA/NCI NIH HHS/United States
GR  - T32 CA009071/CA/NCI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Phthalazines)
RN  - 0 (Piperazines)
RN  - 50SG953SK6 (Mitomycin)
RN  - 7673326042 (Irinotecan)
RN  - Q20Q21Q62J (Cisplatin)
RN  - WOH1JD9AR8 (olaparib)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use
MH  - Biomarkers, Tumor
MH  - Camptothecin/administration & dosage/analogs & derivatives
MH  - Cisplatin/administration & dosage
MH  - Female
MH  - Humans
MH  - Irinotecan
MH  - Male
MH  - Middle Aged
MH  - Mitomycin/administration & dosage
MH  - Neoplasm Staging
MH  - Pancreatic Neoplasms/*drug therapy/genetics/*pathology
MH  - Phthalazines/administration & dosage
MH  - Piperazines/administration & dosage
MH  - Retreatment
MH  - Treatment Outcome
PMC - PMC5546463
OTO - NOTNLM
OT  - BRCA2
OT  - cisplatin
OT  - irinotecan
OT  - olaparib
OT  - pancreatic cancer
EDAT- 2017/04/30 06:00
MHDA- 2018/03/30 06:00
PMCR- 2017/07/04
CRDT- 2017/04/29 06:00
PHST- 2016/02/24 00:00 [received]
PHST- 2017/03/13 00:00 [accepted]
PHST- 2017/04/30 06:00 [pubmed]
PHST- 2018/03/30 06:00 [medline]
PHST- 2017/04/29 06:00 [entrez]
PHST- 2017/07/04 00:00 [pmc-release]
AID - 17237 [pii]
AID - 10.18632/oncotarget.17237 [doi]
PST - ppublish
SO  - Oncotarget. 2017 Jul 4;8(27):44073-44081. doi: 10.18632/oncotarget.17237.