Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

The Addition of Chloroquine to Chemoradiation for Glioblastoma,

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02432417
Recruitment Status : Not yet recruiting
First Posted : May 4, 2015
Last Update Posted : August 14, 2020
Sponsor:
Information provided by (Responsible Party):
Maastricht Radiation Oncology

Tracking Information
First Submitted Date  ICMJE April 9, 2015
First Posted Date  ICMJE May 4, 2015
Last Update Posted Date August 14, 2020
Estimated Study Start Date  ICMJE January 2022
Estimated Primary Completion Date January 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 28, 2015)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 28, 2015)
  • Overall survival [ Time Frame: 2 years after start of study treatment ]
    Randomization until death by any cause
  • 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
  • Gene mutation, deletion or amplification [ Time Frame: 2 years ]
    O6-methylguanine-DNA-methyltransferase (MGMT), isocitrate dehydrogenase (IDH) and EGFRvIII in tumor tissue
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Addition of Chloroquine to Chemoradiation for Glioblastoma,
Official Title  ICMJE A Phase II Randomized Controlled Trial for the Addition of Chloroquine, an Autophagy Inhibitor, to Concurrent Chemoradiation for Newly Diagnosed Glioblastoma
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).

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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • Astrocytoma, Grade IV
Intervention  ICMJE 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
Study Arms  ICMJE
  • 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).

    Intervention: Drug: Chloroquine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: April 28, 2015)
156
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2024
Estimated Primary Completion Date January 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Inge Compter, MD 088-44556666 Inge.Compter@maastro.nl
Contact: Danielle Eekers, MD 088-44556666 Danielle.Eekers@maastro.nl
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02432417
Other Study ID Numbers  ICMJE CHLOROBRAINII
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Maastricht Radiation Oncology
Study Sponsor  ICMJE Maastricht Radiation Oncology
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Philippe Lambin, prof. Maastro Clinic, The Netherlands
PRS Account Maastricht Radiation Oncology
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP