425P - CHLOROBRAIN phase IB trial: The addition of chloroquine, an autophagy inhibitor, to concurrent radiation and temozolomide for newly diagnosed glioblastoma

Abstract

BackgroundTreatment 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. MethodsThis 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 75mg/m2/day) until the end of RT. Toxicity was scored according to the CTCAE 4.0. Molecular markers were identified on paraffin embedded tissue. ResultsThirteen 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: 425PSerious adverse events grade I - V - Adverse events possibly/likely related to chloroquine are presented with an *.Table: 425PToxicityGrade 1Grade 2Grade 3Grade 4Grade 5Blurred Vision*1Confusion1Electrocardiogram (ECG) QT corrected interval prolonged*11Fall (trauma capitis)*1Hypercalcemia1Nausea/vomiting*33Seizure1Thromboembolic event11 ConclusionsA 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 identificationThe study was approved by the Medical Review Ethics Committee Maastricht UMC+: #NL52723.068.15/METC153051. (NCT02378532). Legal entity responsible for the studyThe authors. FundingStichting StopHersentumoren. DisclosureAll authors have declared no conflicts of interest.