Phase I and Pharmacologic Study of Olaparib in Combination with High-dose Radiotherapy with and without Concurrent Cisplatin for Non-Small Cell Lung Cancer.
Aged
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Carcinoma, Non-Small-Cell Lung
/ pathology
Chemoradiotherapy
/ mortality
Cisplatin
/ administration & dosage
Female
Follow-Up Studies
Humans
Lung Neoplasms
/ pathology
Male
Maximum Tolerated Dose
Middle Aged
Phthalazines
/ administration & dosage
Piperazines
/ administration & dosage
Prognosis
Radiotherapy Dosage
Survival Rate
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 03 2021
01 03 2021
Historique:
received:
03
07
2020
revised:
26
10
2020
accepted:
23
11
2020
pubmed:
3
12
2020
medline:
11
2
2022
entrez:
2
12
2020
Statut:
ppublish
Résumé
To identify an MTD of olaparib, a PARP inhibitor, in combination with loco-regional radiotherapy with/without cisplatin for the treatment of non-small cell lung cancer (NSCLC). Olaparib dose was escalated in two groups: radiotherapy (66 Gy/24 fractions in 2.75 Gy/fraction) with and without daily cisplatin (6 mg/m Twenty-eight patients with loco-regional or oligometastatic disease (39%) were treated: 11 at olaparib 25 mg twice daily and 17 at 25 mg once daily. The lowest dose level with cisplatin was above the MTD due to hematologic and late esophageal DLT. The MTD without cisplatin was olaparib 25 mg once daily. At a latency of 1-2.8 years, severe pulmonary adverse events (AE) were observed in 5 patients across all dose levels, resulting in 18% grade 5 pulmonary AEs. Exploratory analyses indicate an association with the radiation dose to the lungs. At the MTD, olaparib reduced PAR levels by more than 95% and abolished radiation-induced PARylation. Median follow-up of survivors was 4.1 years. Two-year loco-regional control was 84%, median overall survival in patients with locally advanced NSCLC was 28 months. Combined mildly hypofractionated radiotherapy and low-dose daily cisplatin and olaparib was not tolerable due to esophageal and hematologic toxicity. Severe pulmonary toxicity was observed as well, even without cisplatin. More conformal radiotherapy schedules with improved pulmonary and esophageal sparing should be explored.
Identifiants
pubmed: 33262140
pii: 1078-0432.CCR-20-2551
doi: 10.1158/1078-0432.CCR-20-2551
doi:
Substances chimiques
Phthalazines
0
Piperazines
0
Cisplatin
Q20Q21Q62J
olaparib
WOH1JD9AR8
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1256-1266Informations de copyright
©2020 American Association for Cancer Research.
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