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The Addition of Chloroquine to Chemoradiation for Glioblastoma,

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ClinicalTrials.gov Identifier: NCT02432417
Recruitment Status : Not yet recruiting
First Posted : May 4, 2015
Last Update Posted : March 21, 2018
Sponsor:
Information provided by (Responsible Party):
Maastricht Radiation Oncology

Brief 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).


Condition or disease Intervention/treatment Phase
Glioblastoma Astrocytoma, Grade IV Drug: Chloroquine Phase 2

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).


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 156 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Randomized Controlled Trial for the Addition of Chloroquine, an Autophagy Inhibitor, to Concurrent Chemoradiation for Newly Diagnosed Glioblastoma
Estimated Study Start Date : January 2020
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2024


Arm Intervention/treatment
No Intervention: Standard
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

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
CQ will start with one week before the start of radiotherapy and end on the last day of radiotherapy.
Other Name: A-CQ




Primary Outcome Measures :
  1. Six-month progression-free survival [ Time Frame: Six months after start of study treatment ]
    The absence of documented disease progression (clinical or radiological) or death due to any cause within six months from randomization


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 2 years after start of study treatment ]
    Randomization until death by any cause

  2. Adverse Events (AE) and serious AEs [ Time Frame: 2 years after start of study treatment ]
    Acute and late toxic effects are scored according to Common Toxicity Criteria for Adverse Effects (CTCAE) 4.0

  3. Gene mutation, deletion or amplification [ Time Frame: 2 years ]
    O6-methylguanine-DNA-methyltransferase (MGMT), isocitrate dehydrogenase (IDH) and EGFRvIII in tumor tissue

  4. Tumor hypoxia [ Time Frame: Six months after start of study treatment ]
    Quantitative and qualitative assessment of [18F]HX4-PET obtained before treatment and one week after the start of CQ



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02432417


Contacts
Contact: Inge Compter, MD 088-44556666 Inge.Compter@maastro.nl
Contact: Danielle Eekers, MD 088-44556666 Danielle.Eekers@maastro.nl

Sponsors and Collaborators
Maastricht Radiation Oncology
Investigators
Principal Investigator: Philippe Lambin, prof. Maastro Clinic, The Netherlands

Publications:
Responsible Party: Maastricht Radiation Oncology
ClinicalTrials.gov Identifier: NCT02432417     History of Changes
Other Study ID Numbers: CHLOROBRAINII
First Posted: May 4, 2015    Key Record Dates
Last Update Posted: March 21, 2018
Last Verified: March 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Maastricht Radiation Oncology:
Glioblastoma
Autophagy
EGFR
EGFRvIII
Chloroquine
Radiotherapy
Temozolomide

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Chloroquine
Chloroquine diphosphate
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antimalarials
Antirheumatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Filaricides
Antinematodal Agents
Anthelmintics