Chloroquine trial: ClinicalTrials.gov Identifier: NCT02378532

Improving the outcome of Glioblastoma patients with anti-malaria medication 

Solid tumours are very heterogeneous and usually have areas with low oxygen or hypoxia. Cells with low oxygen are more resistant to therapy and limit treatment efficacy. Cancer cells survive the lack of oxygen through activation of autophagy (from the Greek auto-, "self" and phagein, "to eat") a natural, recycling mechanism that is used to produce energy, and liberation of essential ‘building materials’.
 
One way to block autophagy is to administer the anti-malaria drug chloroquine  which blocks the final degradative component of autophagy. We observed that mice with tumours of glioblastoma origin, treated with chloroquine, have reduced tumor areas with low oxygen and are therefore more responsive to radiation therapy than tumors treated with radiation alone. Furthermore, we found that hypoxic tumor positive for the oncogene EGFRvIII, are even more dependent to autophagy and therefore more responsive to chloroquine treatment.
 
Those exciting results have been confirmed in an existing small randomized phase II trial where a low dose chloroquine was combined with surgery, radiotherapy and carmustine treatment. Reanalyses of those biopsies confirmed our previous findings that chloroquine improves survival of all GBM patients however, patients with EGFRv3 expressing GBM benefited the most.
 
Chloroquine has been registered at EMEA and at the FDA with an orphan drug designation for GBM. A phase 1 clinical trial in GBM patients is currently in progress to determine the highest safe dose of chloroquine and shows very promising results with excellent tolerance. The logical next step is the initiation of a multicentric randomized phase II clinical trial in GBM patients. The patients within the experimental arm will be treated with surgery, radiotherapy, temozolomide and chloroquine.
 
The trial will be complemented by an ambitious biomarker study before, during and after therapy, including EGFRvIII status, state of the art MR-based Radiomics study and exosome–based blood biomarkers.
 
Patients with a glioblastoma (GBM) have a poor prognosis with a median survival of 14.6 months after maximal treatment with a resection and chemoradiation. Since the pivotal trial evaluating the effect of temozolomide (TMZ), overall survival has not increased.
 
Treatment of GBM xenografts in vivo with chloroquine (CQ), an antimalarial agent, has been shown to reduce the hypoxic fraction and sensitizes tumors to radiation. Epidermal growth factor receptor (EGFR) amplification or mutation is regularly observed GBM and is thought to be a major contributor to radioresistance. The most common EGFR mutation in GBM (EGFRvIII) is present in 50-60% of patients whose tumor shows amplification of EGFR. EGFR provides cells with a survival advantage through autophagy when exposed to stresses such as hypoxia and nutrient starvation. This effect is even more pronounced in EGFRvIII overexpressing tumors. Previously, the potential effect CQ has been demonstrated in a small randomized controlled trial in GBM treated with radiotherapy and carmustine, which showed a trend towards increased overall survival. However, as the intracellular effects of chloroquine are dose-dependent the maximum tolerated dose for CQ in combination with concurrent radiotherapy with daily temozolomide needs to be established.