The Addition of Chloroquine to Chemoradiation for Glioblastoma,
Status:
Not yet recruiting
Trial end date:
2024-01-01
Target enrollment:
Participant gender:
Summary
Glioblastomas (GBM) are the most common type of primary brain tumors with an annual incidence
of approximately 500 patients in the Netherlands. Despite extensive treatment including a
resection, radiation therapy and chemotherapy, the median overall survival is only 14.6
months.
Epidermal growth factor receptor (EGFR) amplification or mutation is regularly observed in
GBM and is thought to be a major contributor to resistance to radiotherapy and chemotherapy.
The most common EGFR mutation in GBM (EGFRvIII) is present in 30-50% of GBM.
Previously MAASTRO lab has shown that expression of EGFRvIII provides GBM cells with a
survival advantage when exposed to stress factors such as hypoxia and nutrient deprivation.
These metabolic stress factors activate a lysosomal degradation pathway, known as autophagy.
Inhibition of autophagy sensitizes cells to hypoxia, reduces the viable hypoxic fraction in
tumors with > 40% and subsequently sensitizes these tumors to irradiation.
Chloroquine (CQ) is a potent autophagy blocker and is the most widely investigated substance
in this context. Previously, the effect of CQ has been demonstrated in a small randomized
controlled trial in GBM treated with radiotherapy and carmustine. Although not statistically
significantly different, the rate of death over time was approximately half as large in
patients receiving CQ as in patients receiving placebo. The intracellular effects of CQ are
dose-dependent. Therefore, the authors suggest an increase in daily dose of CQ may be
necessary. Furthermore, the combination of CQ with TMZ may induce more damage to the
neoplastic cells.
In the phase I part of this trial the recommended dose of CQ in combination with radiotherapy
and temozolomide will be tested. In the phase II part of the trial patients with a
histologically confirmed GBM will be randomized between standard treatment consisting of
concurrent radiotherapy with temozolomide and adjuvant temozolomide (arm A) and standard
treatment plus CQ (arm B).