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Poster Display session 1

5759 - CHLOROBRAIN phase IB trial: The addition of chloroquine, an autophagy inhibitor, to concurrent radiation and temozolomide for newly diagnosed glioblastoma

Date

28 Sep 2019

Session

Poster Display session 1

Topics

Tumour Site

Central Nervous System Malignancies

Presenters

Inge Compter

Citation

Annals of Oncology (2019) 30 (suppl_5): v143-v158. 10.1093/annonc/mdz243

Authors

I. Compter1, D. Eekers1, A. Hoeben2, K. Rouschop1, B.J. Reymen1, L. Ackermans3, J. Beckervordersantforth4, N. Bauer5, M. Anten6, P. Wesseling7, A. Postma8, D. De Ruysscher1, P. Lambin9

Author affiliations

  • 1 Dept. Of Radiation Oncology, Grow- School For Oncology And Developmental Biology, Maastricht University Medical Centre, Maastro Clinic, 6229 ET - Maastricht/NL
  • 2 Dept. Of Internal Medicine, Div. Of Medical Oncology, Grow - School For Oncology And Developmental Biology, Maastricht University Medical Center (MUMC), 6202 AZ - Maastricht/NL
  • 3 Dept. Of Neurosurgery, Maastricht University Medical Center (MUMC), 6202 AZ - Maastricht/NL
  • 4 Dept. Of Pathology, Maastricht University Medical Center (MUMC), 6202 AZ - Maastricht/NL
  • 5 Dept. Of Ophthalmology, Maastricht University Medical Center (MUMC), 6202 AZ - Maastricht/NL
  • 6 Dept. Of Neurology, Maastricht University Medical Center (MUMC), 6202 AZ - Maastricht/NL
  • 7 Dept. Of Pathology, Vrije University Medical Centre (VUMC), 1081 HV - Amsterdam/NL
  • 8 Dept. Of Radiology, Maastricht University Medical Center (MUMC), 6202 AZ - Maastricht/NL
  • 9 The D-lab: Decision Support For Precision Medicine, Grow - School For Oncology And Developmental Biology, Maastricht University Medical Center (MUMC), 6229 ET - Maastricht/NL

Resources

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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 *.

ToxicityGrade 1Grade 2Grade 3Grade 4Grade 5
Blurred Vision*1
Confusion1
Electrocardiogram (ECG) QT corrected interval prolonged*11
Fall (trauma capitis)*1
Hypercalcemia1
Nausea/vomiting*33
Seizure1
Thromboembolic event11

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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