Abstract 5759
Background
Treatment of glioblastoma (GBM) xenografts with chloroquine (CQ) has been shown to inhibit autophagy, thereby reducing the hypoxic fraction and sensitizing tumours to radiation. Preclinical evidence shows that EGFRvIII+ GBM may benefit most from CQ because of autophagy dependency. This study explores the safety, pharmacokinetics and maximum tolerated dose (MTD) of CQ in combination with radiotherapy (RT) and concurrent daily temozolomide (TMZ) in patients with a newly diagnosed GBM.
Methods
This study is a single-centre, open label, dose-finding phase I trial (3 + 3 design). Patients received oral CQ once daily one week before the course of concurrent chemoradiation (TMZ 75 mg/m2/day) until the end of RT. Toxicity was scored according to the CTCAE 4.0. Molecular markers were identified on paraffin embedded tissue.
Results
Thirteen patients were included in the study (n = 6:200mg, n = 3:300mg, n = 4:400mg CQ). Tumour characteristics: 7/13 MGMT promotor hypermethylation, 12/13 IDH wildtype, 0/13 1p/19q co-deletion and 7/13 EGFRvIII expression. A total of 44 adverse events possibly/likely related to CQ were registered. Serious adverse events are presented in Table. In the 400mg cohort 2 patients developed ECG QTc prolongation and 1 patient developed irreversible blurred vision. Three patients developed grade III nausea/vomiting (n = 2 300mg, n = 1 200mg) resulting in cessation of TMZ or delay of adjuvant TMZ cycles. Median overall survival is 8,1 months for EGFRvIII – and 13,4 months for EGFRvIII + patients; with 7 patients currently still alive at a median follow-up of 9 months (range 2 – 21).Table: 425P
Serious adverse events grade I - V - Adverse events possibly/likely related to chloroquine are presented with an *.
Toxicity | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Grade 5 |
---|---|---|---|---|---|
Blurred Vision* | 1 | ||||
Confusion | 1 | ||||
Electrocardiogram (ECG) QT corrected interval prolonged* | 1 | 1 | |||
Fall (trauma capitis)* | 1 | ||||
Hypercalcemia | 1 | ||||
Nausea/vomiting* | 3 | 3 | |||
Seizure | 1 | ||||
Thromboembolic event | 1 | 1 |
Conclusions
A daily dose of 200mg CQ was established as the MTD when combined with RT and concurrent TMZ for newly diagnosed GBM. Favorable tolerability and extensive pre-clinical evidence on anti-tumour activity support further clinical phase II and III studies.
Clinical trial identification
The study was approved by the Medical Review Ethics Committee Maastricht UMC+: #NL52723.068.15/METC153051. (NCT02378532).
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Stichting StopHersentumoren.
Disclosure
All authors have declared no conflicts of interest.
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