Clinical Trials /

The Addition of Chloroquine to Chemoradiation for Glioblastoma,

NCT02432417

Description:

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).

Related Conditions:
  • Glioblastoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: CHLOROBRAINII
  • NCT ID: NCT02432417

Conditions

  • Glioblastoma
  • Astrocytoma, Grade IV

Interventions

DrugSynonymsArms
ChloroquineA-CQExperimental arm

Purpose

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

      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).
    

Trial Arms

NameTypeDescriptionInterventions
StandardNo InterventionRadiotherapy 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 armExperimentalRadiotherapy 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).
    • Chloroquine

    Eligibility Criteria

            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
          
    Maximum Eligible Age:70 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

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

    Secondary Outcome Measures

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

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Maastricht Radiation Oncology

    Trial Keywords

    • Glioblastoma
    • Autophagy
    • EGFR
    • EGFRvIII
    • Chloroquine
    • Radiotherapy
    • Temozolomide

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