The Addition of Chloroquine to Chemoradiation for Glioblastoma (CHLOROBRAIN)
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|ClinicalTrials.gov Identifier: NCT02378532|
Recruitment Status : Recruiting
First Posted : March 4, 2015
Last Update Posted : October 4, 2018
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.
|Condition or disease||Intervention/treatment||Phase|
|Glioblastoma Multiforme||Drug: Chloroquine Radiation: Radiotherapy Drug: Temozolomide||Phase 1|
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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||13 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I Trial for the Addition of Chloroquine, an Autophagy Inhibitor, to Concurrent Chemoradiation for Newly Diagnosed Glioblastoma|
|Actual Study Start Date :||August 2016|
|Estimated Primary Completion Date :||May 2019|
|Estimated Study Completion Date :||June 2019|
Experimental: Radiotherapy/Temozolomide + Chloroquine
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.
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.
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.
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.
Other Name: Temodal
- Toxicity (CTC AE 4.0 [ Time Frame: up to 2.5 years ]Determining the MTD of chloroquine as a radiosensitizer
- Pharmacokinetics of chloroquine, desethylchloroquine, bisdesethylchloroquine. Profile parameters will include trough level (Cmin), AUC and elimination half-life. [ Time Frame: up to 2 years ]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.
- Presence of autophagic markers (LC3 and autophagic vesicles) [ Time Frame: up to 2 years ]Evaluation of autophagic markers will be done at baseline, 2 weeks and at the end of chloroquine treatment
- Evaluation of EGFRvIII status in histopathological material [ Time Frame: up to 2 years ]During biopsy or tumor resection, a small piece of tissue will be collected to evaluate EGFRvIII status
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): NCT02378532
|Contact: Inge Compter, MD||+31 88 4455666||Inge.Compter@maastro.nl|
|Contact: Danielle Eekers, MD||+ 31 88 4455666||Danielle.Eekers@maastro.nl|
|Maastricht Radiation Oncology||Recruiting|
|Maastricht, Netherlands, 6202 AZ|
|Principal Investigator:||Dirk De Ruysscher, prof.||Maastro Clinic, The Netherlands|