The Addition of Chloroquine to Chemoradiation for Glioblastoma,

Study Overview
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Brief Summary
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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).

Detailed Description
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This study is a multi-centre randomized controlled, open label, phase II trial for patients with de-novo GBM. Eligible patients will be randomized between arm A and arm B: Arm A (standard): Radiotherapy and chemotherapy according to standard protocol for newly diagnosed GBM. This consists of 30 daily fractions of 2 Gy or 33 fractions in 1.8 Gy to the tumor and surrounding margin in combination with temozolomide 75 mg/m² per os daily (po qd) and six adjuvant cycles of temozolomide 150 - 200 mg/m² po qd. Arm B (experimental): Standard treatment as described under arm A combined with daily intake of 400mg CQ. CQ will start with one week before the start of radiotherapy and end on the last day of radiotherapy. In a single centre exploratory substudy, thirty subjects sequentially recruited within MAASTRO clinic randomized to arm B will be invited to receive two 3-[18F]fluoro- 2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1- yl)propan-1-ol PET-scans ([18F]HX4 ). The first on day -6 (start CQ), the second on day 0 (before the start radiotherapy and TMZ).

Official Title
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A Phase II Randomized Controlled Trial for the Addition of Chloroquine, an Autophagy Inhibitor, to Concurrent Chemoradiation for Newly Diagnosed Glioblastoma

Conditions
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Glioblastoma, Astrocytoma, Grade IV

Intervention / Treatment
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* Drug: Chloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed grade IV supratentorial astrocytoma, IDH wildtype (glioblastoma multiforme) Tumor tissue available for histopathological analysis Diagnosis must have been made by biopsy or resection lower or equal than 3 months prior to study entry 18 - 70 years Karnofsky performance status greater or equal than 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 Ability to swallow and take oral medication. Exclusion Criteria: Prior radiotherapy Prior chemotherapy Pregnancy or breast feeding Recent (less than 3 months) severe cardiac disease (NYHA class greater than 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, 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) 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard<br>Radiotherapy and chemotherapy according to standard protocol for newly diagnosed GBM. This consists of 30 daily fractions of 2 Gray (Gy) or 33 daily fractions of 1.8 Gy to the tumor and surrounding margin in combination with TMZ 75 mg/m² Per os daily (po qd) and six adjuvant cycles of TMZ 150 - 200 mg/m² po qd. | |
| Experimental: Experimental arm<br>Radiotherapy and chemotherapy according to standard protocol for newly diagnosed GBM. This consists of 30 daily fractions of 2 Gray (Gy) or 33 daily fractions of 1.8 Gy to the tumor and surrounding margin in combination with TMZ 75 mg/m² Per os daily (po qd) and six adjuvant cycles of TMZ 150 - 200 mg/m² po qd. In addition this treatment will be combined with a daily intake of the recommended phase two dose (RPTD) of chloroquine (CQ). | Drug: Chloroquine<br>* CQ will start with one week before the start of radiotherapy and end on the last day of radiotherapy.<br>* Other names: A-CQ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-month progression-free survival | The absence of documented disease progression (clinical or radiological) or death due to any cause within six months from randomization | Six months after start of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Randomization until death by any cause | 2 years after start of study treatment | 
| Adverse Events (AE) and serious AEs | Acute and late toxic effects are scored according to Common Toxicity Criteria for Adverse Effects (CTCAE) 4.0 | 2 years after start of study treatment | 
| Gene mutation, deletion or amplification | O6-methylguanine-DNA-methyltransferase (MGMT), isocitrate dehydrogenase (IDH) and EGFRvIII in tumor tissue | 2 years | 
| Tumor hypoxia | Quantitative and qualitative assessment of [18F]HX4-PET obtained before treatment and one week after the start of CQ | Six months after start of study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma, Autophagy, EGFR, EGFRvIII, Chloroquine, Radiotherapy, Temozolomide