Nanoliposomal Irinotecan and Metronomic Temozolomide for Patients With Recurrent Glioblastoma: BrUOG329, A Phase I Brown University Oncology Research Group Trial.
Administration, Metronomic
Adult
Aged
Anorexia
/ chemically induced
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Brain Neoplasms
/ drug therapy
Diarrhea
/ chemically induced
Drug Delivery Systems
/ methods
Female
Glioblastoma
/ drug therapy
Humans
Irinotecan
/ administration & dosage
Liposomes
/ administration & dosage
Male
Maximum Tolerated Dose
Middle Aged
Nanostructures
/ administration & dosage
Neutropenia
/ chemically induced
Temozolomide
/ administration & dosage
Journal
American journal of clinical oncology
ISSN: 1537-453X
Titre abrégé: Am J Clin Oncol
Pays: United States
ID NLM: 8207754
Informations de publication
Date de publication:
01 02 2021
01 02 2021
Historique:
pubmed:
8
12
2020
medline:
3
3
2021
entrez:
7
12
2020
Statut:
ppublish
Résumé
Liposomal formulations may improve the solubility and bioavailability of drugs potentially increasing their ability to cross the blood-brain barrier. We performed a phase I study to determine the maximum tolerated dose and preliminary efficacy of pegylated nanoliposomal irinotecan (nal-IRI)+metronomic temozolomide (TMZ) in patients with recurrent glioblastoma. Patients with glioblastoma who progressed after at least 1 line of therapy were eligible. All patients received TMZ 50 mg/m2/d until disease progression. Three dose levels of nal-IRI were planned, 50, 70, and 80 mg/m2, intravenously every 2 weeks. Patients were accrued in a 3+3 design. The study included a preliminary assessment after the first 13 evaluable patients. The trial would be terminated early if 0 or 1 responses were observed in these patients. Twelve patients were treated over 2 dose levels (nal-IRI 50 and 70 mg/m2). At dose level 2, nal-IRI 70 mg/m2, 2 of 3 patients developed dose-limiting toxicities including 1 patient who developed grade 4 neutropenia and grade 3 diarrhea and anorexia and 1 patient with grade 3 diarrhea, hypokalemia fatigue, and anorexia. Accrual to dose level 1 was expanded to 9 patients. The Drug Safety Monitoring Board (DSMB) reviewed the data of the initial 12 patients-there were 0/12 responses (0%) and the median progression-free survival was 2 months and accrual was halted. The maximum tolerated dose of nal-IRI was 50 mg/m2 every 2 weeks with TMZ 50 mg/m2/d. The dose-limiting toxicities were diarrhea and neutropenia. No activity was seen at interim analysis and the study was terminated.
Sections du résumé
BACKGROUND
Liposomal formulations may improve the solubility and bioavailability of drugs potentially increasing their ability to cross the blood-brain barrier. We performed a phase I study to determine the maximum tolerated dose and preliminary efficacy of pegylated nanoliposomal irinotecan (nal-IRI)+metronomic temozolomide (TMZ) in patients with recurrent glioblastoma.
PATIENTS AND METHODS
Patients with glioblastoma who progressed after at least 1 line of therapy were eligible. All patients received TMZ 50 mg/m2/d until disease progression. Three dose levels of nal-IRI were planned, 50, 70, and 80 mg/m2, intravenously every 2 weeks. Patients were accrued in a 3+3 design. The study included a preliminary assessment after the first 13 evaluable patients. The trial would be terminated early if 0 or 1 responses were observed in these patients.
RESULTS
Twelve patients were treated over 2 dose levels (nal-IRI 50 and 70 mg/m2). At dose level 2, nal-IRI 70 mg/m2, 2 of 3 patients developed dose-limiting toxicities including 1 patient who developed grade 4 neutropenia and grade 3 diarrhea and anorexia and 1 patient with grade 3 diarrhea, hypokalemia fatigue, and anorexia. Accrual to dose level 1 was expanded to 9 patients. The Drug Safety Monitoring Board (DSMB) reviewed the data of the initial 12 patients-there were 0/12 responses (0%) and the median progression-free survival was 2 months and accrual was halted.
CONCLUSIONS
The maximum tolerated dose of nal-IRI was 50 mg/m2 every 2 weeks with TMZ 50 mg/m2/d. The dose-limiting toxicities were diarrhea and neutropenia. No activity was seen at interim analysis and the study was terminated.
Identifiants
pubmed: 33284237
pii: 00000421-202102000-00002
doi: 10.1097/COC.0000000000000780
doi:
Substances chimiques
Liposomes
0
Irinotecan
7673326042
Temozolomide
YF1K15M17Y
Banques de données
ClinicalTrials.gov
['NCT03119064']
Types de publication
Clinical Trial, Phase I
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
49-52Informations de copyright
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest.
Références
Stupp R, Mason WP, Van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant TMZ for glioblastoma. N Engl J Med. 2005;352:987–996.
Taphoorn MJB, Dirven L, Kanner A, et al. Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma a secondary analysis of a randomized clinical trial. JAMA Oncol. 2018;4:495–504.
Franceschi E, Omuro AM, Lassman AB, et al. Salvage TMZ for prior TMZ responders. N Engl J Med. 2005;104:2473–2476.
Wick W, Platten M, Weller M. New (alternative) TMZ regimens for the treatment of glioma. Neuro-Oncology. 2008;11:69–79.
Ko KK, Lee ES, Joe YA, et al. Metronomic treatment of TMZ increases anti-angiogenicity accompanied by down-regulated O6-methylguanine-DNA methyltransferase expression in endothelial cells. Exp Ther Med. 2011;2:343–348.
Woo JY, Yang SH, Lee YS, et al. Continuous low-dose TMZ chemotherapy and microvessel density in recurrent glioblastoma. J Korean Neurosurg Soc. 2015;58:426–431.
Verhoeff JJ, Lavini C, van Linde ME, et al. Bevacizumab and dose-intense TMZ in recurrent high-grade glioma. Ann Oncol. 2010;21:1723–1727.
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733–4740.
Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev. 2010;23:858–883.
Spring BQ, Bryan Sears R, Zheng LZ, et al. A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways. Nat Nanotechnol. 2016;11:378–387.
Noble CO, Krauze MT, Drummond DC, et al. Pharmacokinetics, tumor accumulation and antitumor activity of nanoliposomal irinotecan following systemic treatment of intracranial tumors. Nanomedicine (Lond). 2014;9:2099–2108.
Kushner BH, Kramer K, Modak S, et al. Irinotecan plus TMZ for relapsed or refractory neuroblastoma. J Clin Oncol. 2006;24:5271–5276.
Casey DA, Wexler LH, Merchant MS, et al. Irinotecan and TMZ for Ewing sarcoma: The Memorial Sloan-Kettering experience. Pediatr Blood Cancer. 2009;53:1029–1034.
Blanchette P, Lo A, Ng P, et al. Irinotecan and TMZ in adults with recurrent sarcoma. J Solid Tumors. 2015;5:105–110.
Macdonald DR, Cascino TL, Schold SC, et al. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8:1277–1280.
Rehman SS, Lim K, Wang-Gillam A. Nanoliposomal irinotecan plus fluorouracil and folinic acid: a new treatment option in metastatic pancreatic cancer. Expert Rev Anticancer Ther. 2016;16:485–492.
Wang-Gillam A, Hubner R, Mirakhur B, et al. Dose modifications of liposomal irinotecan (nal-IRI)+5-fluorouracil/leucovorin (5-FU/LV) in NAPOLI-1: impact on efficacy. J Clin Oncol. 2018;36:388.