Abstract

Treatment of glioblastoma xenografts with chloroquine results in macroautophagy/autophagy inhibition, resulting in a reduction of tumor hypoxia and sensitization to radiation. Preclinical data show thatEGFRvIII-expressing glioblastoma may benefit most from chloroquine because of autophagy dependency. This study is the first to explore the safety, pharmacokinetics and maximum tolerated dose of chloroquine in combination with radiotherapy and concurrent daily temozolomide in patients with a newly diagnosed glioblastoma. This study is a single-center, open-label, dose-finding phase I trial. Patients received oral chloroquine daily starting one week before the course of chemoradiation (temozolomide 75 mg/m(2)/d) until the end of radiotherapy (59.4 Gy/33 fractions). Thirteen patients were included in the study (n = 6: 200 mg, n = 3: 300 mg, n = 4: 400 mg chloroquine). A total of 44 adverse events, possibly related to chloroquine, were registered including electrocardiogram QTc prolongation, irreversible blurred vision and nausea/vomiting resulting in cessation of temozolomide or delay of adjuvant cycles. The maximum tolerated dose was 200 mg chloroquine. Median overall survival was 16 months (range 2-32). Median survival was 11.5 months forEGFRvIII- patients and 20 months forEGFRvIII+ patients. A daily dose of 200 mg chloroquine was determined to be the maximum tolerated dose when combined with radiotherapy and concurrent temozolomide for newly diagnosed glioblastoma. Favorable toxicity and promising overall survival support further clinical studies.

Original languageEnglish
Pages (from-to)2604-2612
Number of pages9
JournalAutophagy
Volume17
Issue number9
Early online date20 Sep 2020
DOIs
Publication statusPublished - 2 Sep 2021

Keywords

  • Autophagy
  • brain tumor
  • chloroquine
  • glioblastoma
  • radiotherapy
  • temozolomide
  • ADJUVANT TEMOZOLOMIDE
  • CANCER-CELLS
  • AUTOPHAGY
  • RADIATION
  • COMBINATION
  • EXPRESSION
  • THERAPY
  • EGFR
  • HYDROXYCHLOROQUINE
  • CYTOTOXICITY

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