GlioblastomaPhase 2NCT02432417
The Addition of Chloroquine to Chemoradiation for Glioblastoma,
A Phase 2 study testing Chloroquine in people with Glioblastoma and Astrocytoma, Grade IV, run by Maastricht Radiation Oncology.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Glioblastoma, Astrocytoma, Grade IV
- What is being tested?
- Chloroquine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- 10 Nov 2023to 10 Nov 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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
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- 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
About this study
Official title: A Phase II Randomized Controlled Trial for the Addition of Chloroquine, an Autophagy Inhibitor, to Concurrent Chemoradiation for Newly Diagnosed Glioblastoma
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.
Read more
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).
Read the 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).
- Conditions
- Glioblastoma, Astrocytoma, Grade IV
- Being tested
- Chloroquine
- Keywords
- Glioblastoma, Autophagy, EGFR, EGFRvIII, Chloroquine, Radiotherapy, Temozolomide
- Medical subject headings
- Glioblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ChloroquineDrug
Also called A-CQ
CQ will start with one week before the start of radiotherapy and end on the last day of radiotherapy.
| Study group | Role | What they receive |
|---|---|---|
| Standard | No intervention | 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 arm | Experimental | 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). Receives: Drug: Chloroquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Six months after start of study treatment
Secondary outcomes (4)
Overall survival
Randomization until death by any cause
Measured: 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
Measured: 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
Measured: 2 years
Tumor hypoxia
Quantitative and qualitative assessment of [18F]HX4-PET obtained before treatment and one week after the start of CQ
Measured: Six months after start of study treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 May 2015 (estimated)
- Study start10 Nov 2023
- Primary completion10 Nov 2023
- Study completion10 Nov 2023
Why it stopped: The study was withdrawn due to a lack of funding. The researchers were unable to secure the necessary financial support to continue and complete the trial.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for GlioblastomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Maastricht Radiation Oncology
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Philippe Lambin, prof., Principal investigator, Maastro Clinic, The Netherlands
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02432417
- Sponsor's protocol ID
- CHLOROBRAINII
- Status last verified
- Nov 2023
- First submitted
- 9 Apr 2015
- Last updated
- 18 Nov 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Sotelo J, Briceno E, Lopez-Gonzalez MA. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006 Mar 7;144(5):337-43. doi: 10.7326/0003-4819-144-5-200603070-00008.
PubMed 16520474Jutten B, Keulers TG, Schaaf MB, Savelkouls K, Theys J, Span PN, Vooijs MA, Bussink J, Rouschop KM. EGFR overexpressing cells and tumors are dependent on autophagy for growth and survival. Radiother Oncol. 2013 Sep;108(3):479-83. doi: 10.1016/j.radonc.2013.06.033. Epub 2013 Jul 25.
PubMed 23891088Jutten B, Rouschop KM. EGFR signaling and autophagy dependence for growth, survival, and therapy resistance. Cell Cycle. 2014;13(1):42-51. doi: 10.4161/cc.27518. Epub 2013 Dec 13.
PubMed 24335351Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, Lambin P, van der Kogel AJ, Koritzinsky M, Wouters BG. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest. 2010 Jan;120(1):127-41. doi: 10.1172/JCI40027. Epub 2009 Dec 14.
PubMed 20038797
Study at a glance
From the registry record, last updated by the sponsor on 18 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Randomized Controlled Trial for the Addition of Chloroquine, an Autophagy Inhibitor, to Concurrent Chemoradiation for Newly Diagnosed Glioblastoma
- ClinicalTrials.gov ID
- NCT02432417
- Acronym / sponsor ID
- CHLOROBRAINII
- Conditions
- Glioblastoma, Astrocytoma, Grade IV
- Keywords
- Glioblastoma, Autophagy, EGFR, EGFRvIII, Chloroquine, Radiotherapy, Temozolomide
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: The study was withdrawn due to a lack of funding. The researchers were unable to secure the necessary financial support to continue and complete the trial.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Maastricht Radiation OncologyUniversity, hospital or other
- Study start
- 10 Nov 2023 (actual)
- Primary completion
- 10 Nov 2023 (actual)
- Study completion
- 10 Nov 2023 (actual)
- First posted
- 4 May 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard | No intervention | –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 arm | Experimental | Drug: ChloroquineRadiotherapy 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). |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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
Key exclusion criteria (17 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ChloroquineAlso: A-CQCQ will start with one week before the start of radiotherapy and end on the last day of radiotherapy. | Drug | Experimental arm |
Primary outcome
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
4 secondary outcomes
Overall survival
Time frame: 2 years after start of study treatment
Adverse Events (AE) and serious AEs
Time frame: 2 years after start of study treatment
Gene mutation, deletion or amplification
Time frame: 2 years
Tumor hypoxia
Time frame: Six months after start of study treatment
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Nov 2023.
- Background: PubMed 16520474Sotelo J, Briceno E, Lopez-Gonzalez MA. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006 Mar 7;144(5):337-43. doi: 10.7326/0003-4819-144-5-200603070-00008.
- Background: PubMed 23891088Jutten B, Keulers TG, Schaaf MB, Savelkouls K, Theys J, Span PN, Vooijs MA, Bussink J, Rouschop KM. EGFR overexpressing cells and tumors are dependent on autophagy for growth and survival. Radiother Oncol. 2013 Sep;108(3):479-83. doi: 10.1016/j.radonc.2013.06.033. Epub 2013 Jul 25.
- Background: PubMed 24335351Jutten B, Rouschop KM. EGFR signaling and autophagy dependence for growth, survival, and therapy resistance. Cell Cycle. 2014;13(1):42-51. doi: 10.4161/cc.27518. Epub 2013 Dec 13.
- Background: PubMed 20038797Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, Lambin P, van der Kogel AJ, Koritzinsky M, Wouters BG. The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest. 2010 Jan;120(1):127-41. doi: 10.1172/JCI40027. Epub 2009 Dec 14.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Philippe Lambin, prof. principal investigator
Maastro Clinic, The Netherlands
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Chloroquine in people with Glioblastoma and Astrocytoma, Grade IV, run by Maastricht Radiation Oncology.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 18 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Six-month progression-free survival (time frame: Six months after start of study treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02432417, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Nov 2023.