The Addition of Chloroquine to Chemoradiation for Glioblastoma,

Study 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).

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years - 70 Years
Gender All
More Inclusion & Exclusion 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

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT02432417
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Maastricht Radiation Oncology
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Philippe Lambin, prof.
Principal Investigator Affiliation Maastro Clinic, The Netherlands
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other
Overall Status Not yet recruiting
Countries
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Glioblastoma, Astrocytoma, Grade IV
Additional Details

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).

Arms & Interventions

Arms

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).

Interventions

Drug: - Chloroquine

CQ will start with one week before the start of radiotherapy and end on the last day of radiotherapy.

Contact Information

This trial has no sites locations listed at this time. If you are interested in learning more, you can contact the trial's primary contact:

Inge Compter, MD

Inge.Compter@maastro.nl

088-44556666

For additional contact information, you can also visit the trial on clinicaltrials.gov.

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