Glioblastoma MultiformePhase 1CHLOROBRAINNCT02378532
The Addition of Chloroquine to Chemoradiation for Glioblastoma
A Phase 1 study testing Chloroquine, Radiotherapy and Temozolomide in people with Glioblastoma Multiforme, run by Maastricht Radiation Oncology at 1 site in Netherlands.
Trial summary
Patients with a glioblastoma (GBM) have a poor prognosis with a median survival of 14.6 months after maximal treatment with a resection and chemoradiation. Since the pivotal trial evaluating the effect of temozolomide (TMZ), overall survival has not increased. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Glioblastoma Multiforme
- What is being tested?
- Chloroquine, Radiotherapy and Temozolomide
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 1 siteNetherlands
- Study dates
- Aug 2016to 30 Jul 2019
- Phase
- Phase 1
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed grade IV supratentorial astrocytoma (glioblastoma multiforme)
- Tumor tissue available for histopathological analysis (MGMT, EGFRvIII)
- Diagnosis must have been made by biopsy or resection ≤ 3 months prior to study entry
- 18 years or older
- Karnofsky performance status ≥ 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
Who cannot join
- Prior radiotherapy
- Prior chemotherapy
- Recent (< 3 months) severe cardiac disease (NYHA class >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 (CTC AE 4.0), 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
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- If the subject has clinically significant and uncontrolled major medical condition(s) including but not limited to:
- uncontrolled nausea/vomiting/diarrhea:
- active uncontrolled infection, including HIV and hepatitis (HBV, HCV)
- 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 locations and contacts
1 site in 1 country.
About this study
Official title: A Phase I Trial for the Addition of Chloroquine, an Autophagy Inhibitor, to Concurrent Chemoradiation for Newly Diagnosed Glioblastoma
Patients with a glioblastoma (GBM) have a poor prognosis with a median survival of 14.6 months after maximal treatment with a resection and chemoradiation. Since the pivotal trial evaluating the effect of temozolomide (TMZ), overall survival has not increased.
Treatment of GBM xenografts in vivo with chloroquine (CQ), an antimalarial agent, has been shown to reduce the hypoxic fraction and sensitizes tumors to radiation. Epidermal growth factor receptor (EGFR) amplification or mutation is regularly observed GBM and is thought to be a major contributor to radioresistance. The most common EGFR mutation in GBM (EGFRvIII) is present in 50-60% of patients whose tumor shows amplification of EGFR. EGFR provides cells with a survival advantage through autophagy when exposed to stresses such as hypoxia and nutrient starvation. This effect is even more pronounced in EGFRvIII overexpressing tumors. Previously, the potential effect CQ has been demonstrated in a small randomized controlled trial in GBM treated with radiotherapy and carmustine, which showed a trend towards increased overall survival. However, as the intracellular effects of chloroquine are dose-dependent the maximum tolerated dose for CQ in combination with concurrent radiotherapy with daily temozolomide needs to be established.
Read the detailed description
This trial has been designed as an open label, single center combination phase I trial. The primary objective is to determine the maximum tolerated dose (MTD) for chloroquine (CQ) in combination with concurrent radiotherapy with daily temozolomide in patients with a newly diagnosed GBM.
Eligible patients will receive radiotherapy and chemotherapy according to standard protocol for newly diagnosed GBM. This consists of 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. Treatment will be combined with daily intake of escalating doses of chloroquine. Chloroquine will start with week before the start of radiotherapy and end on the last day of radiotherapy.
The rate of subject entry and escalation to the next dose level will depend upon assessment of the safety profile of patients entered at the previous dose level. Toxicity will be evaluated according to the NCI common Terminology Criteria for Adverse Events (CTCAE), Version 4.0.
The 3 + 3 cohort method is used. A minimum of three patients will be entered at each dose level. All three will be followed during the concomitant radiotherapy and a 4 week observation period before escalation to the next dose level.
The start dose is 200mg chloroquine daily. Before opening the next higher dose level all toxic effects at the preceding dose level will be reviewed and expansion or escalation will be undertaken as appropriate
- Conditions
- Glioblastoma Multiforme
- Being tested
- Chloroquine, Radiotherapy, Temozolomide
- Keywords
- Glioblastoma, Chloroquine, Autophagy, EGFRvIII, 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
Three cohorts of 3 patients will receive chloroquine in escalating doses (3 dose levels: 200 mg up to 600 mg daily) during standard treatment (radiotherapy and temozolomide) for newly diagnosed GBM. Extra patients can be added to a cohort in case of dose limiting toxicity, resulting in a maximum of 6 patients per dose level. Based on the results of the DSMB an additional leven of 300mg was added.
RadiotherapyRadiation
Patients will receive megavoltage radiotherapy in a conventionally fractionated regimen of 59.4 Gy in 33 fractions in 6.5 weeks, using modern computer-based treatment planning and delivery techniques. Treatment should start within 6 weeks of surgery.
TemozolomideDrug
Also called Temodal
Patients will take TMZ 75 mg/m² po qd during the course of radiotherapy six adjuvant cycles of TMZ. After a 4 week break, patients will receive up to six cycles of adjuvant oral TMZ 150 - 200 mg/m² po qd for 5 days every 28 days. The starting dose is 150 mg/m² po qd. At the start of cycle 2 the dose will be escalated to 200mg/m2, if the CTC non-hematologic toxicity for cycle 1 is grade ≤2 (except for alopecia, nausea, and vomiting), absolute neutrophil count is ≥1.5 x 109/L and the platelet count ≥ 100 x 109/L.
| Study group | Role | What they receive |
|---|---|---|
| Radiotherapy/Temozolomide + Chloroquine | Experimental | Eligible patients will receive radiotherapy and chemotherapy according to standard protocol for newly diagnosed GBM.
Chloroquine will be escalated in 3 dose-levels (200mg, 400mg and 600mg) up each containing a minimum of 3 and a maximum of 6 patients. Based on the results of the DSMB, an additional level of 300mg was added. Receives: Drug: Chloroquine; Radiation: Radiotherapy; Drug: Temozolomide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Toxicity (CTC AE 4.0
Determining the MTD of chloroquine as a radiosensitizer
Measured: up to 2.5 years
Secondary outcomes (3)
Pharmacokinetics of chloroquine, desethylchloroquine, bisdesethylchloroquine. Profile parameters will include trough level (Cmin), AUC and elimination half-life.
Pharmacokinetic sampling will be done at the start of week 1 and week 2 to determine the interpatient variability and steady state and at the end of radiotherapy/TMZ/CQ and before the start of adjuvant temozolomide in order to determine the time to eliminate CQ from the body.
Measured: up to 2 years
Presence of autophagic markers (LC3 and autophagic vesicles)
Evaluation of autophagic markers will be done at baseline, 2 weeks and at the end of chloroquine treatment
Measured: up to 2 years
Evaluation of EGFRvIII status in histopathological material
During biopsy or tumor resection, a small piece of tissue will be collected to evaluate EGFRvIII status
Measured: up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Mar 2015 (estimated)
- Study startAug 2016
- Primary completion17 Jan 2019
- Study completion30 Jul 2019
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 Glioblastoma MultiformeStudies 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 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Maastricht Radiation Oncology
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Dirk De Ruysscher, prof., Principal investigator, Maastro Clinic, The Netherlands
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02378532
- Sponsor's protocol ID
- CHLOROBRAIN
- Acronym
- CHLOROBRAIN
- Status last verified
- Jan 2020
- First submitted
- 12 Feb 2015
- Last updated
- 23 Jan 2020
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Jutten 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 20038797Sotelo 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 23891088
Study at a glance
From the registry record, last updated by the sponsor on 23 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Trial for the Addition of Chloroquine, an Autophagy Inhibitor, to Concurrent Chemoradiation for Newly Diagnosed Glioblastoma
- ClinicalTrials.gov ID
- NCT02378532
- Acronym / sponsor ID
- CHLOROBRAIN / CHLOROBRAIN
- Conditions
- Glioblastoma Multiforme
- Keywords
- Glioblastoma, Chloroquine, Autophagy, EGFRvIII, Radiotherapy, Temozolomide
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- Maastricht Radiation OncologyUniversity, hospital or other
- Study start
- Aug 2016 (actual)
- Primary completion
- 17 Jan 2019 (actual)
- Study completion
- 30 Jul 2019 (actual)
- First posted
- 4 Mar 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.
Patients with a glioblastoma (GBM) have a poor prognosis with a median survival of 14.6 months after maximal treatment with a resection and chemoradiation. Since the pivotal trial evaluating the effect of temozolomide (TMZ), overall survival has not increased.
Treatment of GBM xenografts in vivo with chloroquine (CQ), an antimalarial agent, has been shown to reduce the hypoxic fraction and sensitizes tumors to radiation. Epidermal growth factor receptor (EGFR) amplification or mutation is regularly observed GBM and is thought to be a major contributor to radioresistance. The most common EGFR mutation in GBM (EGFRvIII) is present in 50-60% of patients whose tumor shows amplification of EGFR. EGFR provides cells with a survival advantage through autophagy when exposed to stresses such as hypoxia and nutrient starvation. This effect is even more pronounced in EGFRvIII overexpressing tumors. Previously, the potential effect CQ has been demonstrated in a small randomized controlled trial in GBM treated with radiotherapy and carmustine, which showed a trend towards increased overall survival. However, as the intracellular effects of chloroquine are dose-dependent the maximum tolerated dose for CQ in combination with concurrent radiotherapy with daily temozolomide needs to be established.
Detailed description
This trial has been designed as an open label, single center combination phase I trial. The primary objective is to determine the maximum tolerated dose (MTD) for chloroquine (CQ) in combination with concurrent radiotherapy with daily temozolomide in patients with a newly diagnosed GBM.
Eligible patients will receive radiotherapy and chemotherapy according to standard protocol for newly diagnosed GBM. This consists of 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. Treatment will be combined with daily intake of escalating doses of chloroquine. Chloroquine will start with week before the start of radiotherapy and end on the last day of radiotherapy.
The rate of subject entry and escalation to the next dose level will depend upon assessment of the safety profile of patients entered at the previous dose level. Toxicity will be evaluated according to the NCI common Terminology Criteria for Adverse Events (CTCAE), Version 4.0.
The 3 + 3 cohort method is used. A minimum of three patients will be entered at each dose level. All three will be followed during the concomitant radiotherapy and a 4 week observation period before escalation to the next dose level.
The start dose is 200mg chloroquine daily. Before opening the next higher dose level all toxic effects at the preceding dose level will be reviewed and expansion or escalation will be undertaken as appropriate
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Radiotherapy/Temozolomide + Chloroquine | Experimental | Drug: Chloroquine, Radiation: Radiotherapy, Drug: TemozolomideEligible patients will receive radiotherapy and chemotherapy according to standard protocol for newly diagnosed GBM. Chloroquine will be escalated in 3 dose-levels (200mg, 400mg and 600mg) up each containing a minimum of 3 and a maximum of 6 patients. Based on the results of the DSMB, an additional level of 300mg was added. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Histologically confirmed grade IV supratentorial astrocytoma (glioblastoma multiforme)
- Tumor tissue available for histopathological analysis (MGMT, EGFRvIII)
- Diagnosis must have been made by biopsy or resection ≤ 3 months prior to study entry
- 18 years or older
- Karnofsky performance status ≥ 70
Key exclusion criteria (18 listed)
- Prior radiotherapy
- Prior chemotherapy
- Recent (< 3 months) severe cardiac disease (NYHA class >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 (CTC AE 4.0), or asymptomatic sustained ventricular tachycardia. Asymptomatic atrial fibrillation controlled on medication is allowed.
- Cardiac conduction disturbances or medication potentially causing them
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 |
|---|---|---|
| ChloroquineThree cohorts of 3 patients will receive chloroquine in escalating doses (3 dose levels: 200 mg up to 600 mg daily) during standard treatment (radiotherapy and temozolomide) for newly diagnosed GBM. Extra patients can be added to a cohort in case of dose limiting toxicity, resulting in a maximum of 6 patients per dose level. Based on the results of the DSMB an additional leven of 300mg was added. | Drug | Radiotherapy/Temozolomide + Chloroquine |
| RadiotherapyPatients will receive megavoltage radiotherapy in a conventionally fractionated regimen of 59.4 Gy in 33 fractions in 6.5 weeks, using modern computer-based treatment planning and delivery techniques. Treatment should start within 6 weeks of surgery. | Radiation | Radiotherapy/Temozolomide + Chloroquine |
| TemozolomideAlso: TemodalPatients will take TMZ 75 mg/m² po qd during the course of radiotherapy six adjuvant cycles of TMZ. After a 4 week break, patients will receive up to six cycles of adjuvant oral TMZ 150 - 200 mg/m² po qd for 5 days every 28 days. The starting dose is 150 mg/m² po qd. At the start of cycle 2 the dose will be escalated to 200mg/m2, if the CTC non-hematologic toxicity for cycle 1 is grade ≤2 (except for alopecia, nausea, and vomiting), absolute neutrophil count is ≥1.5 x 109/L and the platelet count ≥ 100 x 109/L. | Drug | Radiotherapy/Temozolomide + Chloroquine |
Primary outcome
Toxicity (CTC AE 4.0
Time frame: up to 2.5 years
Determining the MTD of chloroquine as a radiosensitizer
3 secondary outcomes
Pharmacokinetics of chloroquine, desethylchloroquine, bisdesethylchloroquine. Profile parameters will include trough level (Cmin), AUC and elimination half-life.
Time frame: up to 2 years
Presence of autophagic markers (LC3 and autophagic vesicles)
Time frame: up to 2 years
Evaluation of EGFRvIII status in histopathological material
Time frame: up to 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jan 2020.
- 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.
- Results publication: 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.
- Results publication: 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.
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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.
Dirk De Ruysscher, prof. principal investigator
Maastro Clinic, The Netherlands
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Chloroquine, Radiotherapy and Temozolomide in people with Glioblastoma Multiforme, run by Maastricht Radiation Oncology at 1 site in Netherlands.
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 12 inclusion and 18 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: finished, as of the sponsor's last update on 23 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Toxicity (CTC AE 4.0 (time frame: up to 2.5 years). 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 NCT02378532, 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 23 Jan 2020.