A phase 1 study of veliparib, a PARP-1/2 inhibitor, with gemcitabine and radiotherapy in locally advanced pancreatic cancer.
Aged
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Benzimidazoles
/ administration & dosage
Combined Modality Therapy
Deoxycytidine
/ administration & dosage
Female
Humans
Male
Microsatellite Instability
Middle Aged
Mutation
Neoplasm Metastasis
Neoplasm Staging
Pancreatic Neoplasms
/ mortality
Poly (ADP-Ribose) Polymerase-1
/ antagonists & inhibitors
Poly(ADP-ribose) Polymerase Inhibitors
/ administration & dosage
Poly(ADP-ribose) Polymerases
Prognosis
Radiotherapy
/ methods
Treatment Outcome
Gemcitabine
Gemcitabine
Pancreas cancer
Parp inhibitor
Radiation
Veliparib
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Feb 2019
Feb 2019
Historique:
received:
06
12
2018
revised:
29
12
2018
accepted:
29
12
2018
pubmed:
13
1
2019
medline:
27
6
2019
entrez:
13
1
2019
Statut:
ppublish
Résumé
Locally advanced pancreatic cancer (LAPC) has a dismal prognosis with current treatment modalities and one-third of patients die from local progression of disease. Preclinical studies with orthotopic PC demonstrated dramatic synergy between radiotherapy (RT) and the poly(ADP-ribose) polymerase-1/2 inhibitor (PARPi), veliparib. We conducted a phase I trial of gemcitabine, radiotherapy and dose-escalated veliparib in LAPC. This was a single institution investigator-initiated open-label, single-arm phase 1 clinical trial (NCT01908478). Weekly gemcitabine with daily IMRT and veliparib dose escalated using a Bayesian adaptive design were administered in treatment naïve LA or borderline resectable PC. The primary end point was identification of the MTD. Secondary endpoints included efficacy, characterization of PAR levels using ELISA, DDR alterations with targeted next generation sequencing and transcriptome analysis, tumor mutation burden (TMB) and microsatellite instability (MSI) status. Thirty patients were enrolled. The MTD of veliparib was 40 mg BID with gemcitabine 400 mg/m This is the first report of a PARPi-chemoradiotherapy combination in PC. The regimen was safe, tolerable at the RP2D, and clinically active as an upfront treatment strategy in patients biologically unselected by upfront chemotherapy. Expression of the DDR transcripts, PARP3 and RBX1, were associated with OS suggesting validation in a follow up phase 2 study. FUND: Phase One Foundation; National Institutes of Health [1R01CA188480-01A1, P01 CA098912]. Veliparib was provided by Abbvie.
Sections du résumé
BACKGROUND
BACKGROUND
Locally advanced pancreatic cancer (LAPC) has a dismal prognosis with current treatment modalities and one-third of patients die from local progression of disease. Preclinical studies with orthotopic PC demonstrated dramatic synergy between radiotherapy (RT) and the poly(ADP-ribose) polymerase-1/2 inhibitor (PARPi), veliparib. We conducted a phase I trial of gemcitabine, radiotherapy and dose-escalated veliparib in LAPC.
METHODS
METHODS
This was a single institution investigator-initiated open-label, single-arm phase 1 clinical trial (NCT01908478). Weekly gemcitabine with daily IMRT and veliparib dose escalated using a Bayesian adaptive design were administered in treatment naïve LA or borderline resectable PC. The primary end point was identification of the MTD. Secondary endpoints included efficacy, characterization of PAR levels using ELISA, DDR alterations with targeted next generation sequencing and transcriptome analysis, tumor mutation burden (TMB) and microsatellite instability (MSI) status.
FINDINGS
RESULTS
Thirty patients were enrolled. The MTD of veliparib was 40 mg BID with gemcitabine 400 mg/m
INTERPRETATION
CONCLUSIONS
This is the first report of a PARPi-chemoradiotherapy combination in PC. The regimen was safe, tolerable at the RP2D, and clinically active as an upfront treatment strategy in patients biologically unselected by upfront chemotherapy. Expression of the DDR transcripts, PARP3 and RBX1, were associated with OS suggesting validation in a follow up phase 2 study. FUND: Phase One Foundation; National Institutes of Health [1R01CA188480-01A1, P01 CA098912]. Veliparib was provided by Abbvie.
Identifiants
pubmed: 30635165
pii: S2352-3964(18)30637-6
doi: 10.1016/j.ebiom.2018.12.060
pmc: PMC6412162
pii:
doi:
Substances chimiques
Benzimidazoles
0
Poly(ADP-ribose) Polymerase Inhibitors
0
veliparib
01O4K0631N
Deoxycytidine
0W860991D6
PARP1 protein, human
EC 2.4.2.30
PARP2 protein, human
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
Gemcitabine
0
Types de publication
Clinical Trial, Phase I
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
375-381Subventions
Organisme : NCRR NIH HHS
ID : UL1 RR033176
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188480
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA098912
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000124
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA191139
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
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