The Addition of Chloroquine to Chemoradiation for Glioblastoma

• Status: Completed
• Trial end date: 2019-07-30
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Maastricht Radiation Oncology
• Treatments: Chloroquine; Chloroquine diphosphate; Dacarbazine; Temozolomide

Criteria

Inclusion Criteria:

• Histologically confirmed grade IV supratentorial astrocytoma (glioblastoma multiforme)

• Tumor tissue available for histopathological analysis (MGMT, EGFRvIII)

• Diagnosis must have been made by biopsy or resection ≤ 3 months prior to study entry

• 18 years or older

• Karnofsky performance status ≥ 70

• Absolute neutrophil count at least 1.5 x 109/L and platelets at least 100 x109/L

• Adequate renal function

• Adequate hepatic function

• absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

• Females must have negative results for pregnancy tests performed

• No breast feeding.

• If male, subject must be surgically sterile or practicing a method of contraception

Exclusion Criteria:

• Prior radiotherapy

• Prior chemotherapy

• Recent (< 3 months) severe cardiac disease (NYHA class >1) (congestive heart failure, infarction)

• History of cardiac arrythmia (multifocal premature ventricular contractions, uncontrolled atrial fibrillation, bigeminy, trigeminy, ventricular tachycardia) which is symptomatic and requiring treatment (CTC AE 4.0), or asymptomatic sustained ventricular tachycardia. Asymptomatic atrial fibrillation controlled on medication is allowed.

• Cardiac conduction disturbances or medication potentially causing them

• Treatment with investigational drugs in 4 weeks prior to or during this study

• If the subject has clinically significant and uncontrolled major medical condition(s) including but not limited to:

• uncontrolled nausea/vomiting/diarrhea:

• active uncontrolled infection, including HIV and hepatitis (HBV, HCV)

• psychiatric illness/social situation that would limit compliance with study requirements

• any medical condition, with the opinion of the study investigator, places the subject at an unacceptably high risk for toxicities.

• The subject has had another active malignancy within the past 3 years except for any cancer in situ that the principal Investigator considers to be cured.

• Chronic systemic immune therapy (with the exception of corticosteroids)

• Concurrent cytochrome P450 enzyme-inducing anticonvulsant drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, or oxcarbazepine)

• Known glucose-6-phosphate dehydrogenase deficiency

• Psoriasis or porphyria

• Known hypersensitivity to 4-aminoquinoline compound

• Retinal or visual field changes unrelated to the tumor location prior to 4-aminoquinoline compound use