Back to results

The Addition of Chloroquine to Chemoradiation for Glioblastoma,

Primary Purpose

Glioblastoma, Astrocytoma, Grade IV

Status

Not yet recruiting

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Chloroquine

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring Glioblastoma, Autophagy, EGFR, EGFRvIII, Chloroquine, Radiotherapy, Temozolomide

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

Standard

Experimental arm

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Overall survival

Randomization until death by any cause

Adverse Events (AE) and serious AEs

Acute and late toxic effects are scored according to Common Toxicity Criteria for Adverse Effects (CTCAE) 4.0

Gene mutation, deletion or amplification

O6-methylguanine-DNA-methyltransferase (MGMT), isocitrate dehydrogenase (IDH) and EGFRvIII in tumor tissue

Tumor hypoxia

Quantitative and qualitative assessment of [18F]HX4-PET obtained before treatment and one week after the start of CQ

Full Information

NCT ID

NCT02432417

First Posted

April 9, 2015

Last Updated

April 11, 2022

Sponsor

Maastricht Radiation Oncology

1. Study Identification

Unique Protocol Identification Number

NCT02432417

Brief Title

The Addition of Chloroquine to Chemoradiation for Glioblastoma,

Official Title

A Phase II Randomized Controlled Trial for the Addition of Chloroquine, an Autophagy Inhibitor, to Concurrent Chemoradiation for Newly Diagnosed Glioblastoma

Study Type

Interventional

2. Study Status

Record Verification Date

April 2022

Overall Recruitment Status

Not yet recruiting

Study Start Date

January 2023 (Anticipated)

Primary Completion Date

January 2025 (Anticipated)

Study Completion Date

January 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Maastricht Radiation Oncology

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glioblastoma, Astrocytoma, Grade IV

Keywords

Glioblastoma, Autophagy, EGFR, EGFRvIII, Chloroquine, Radiotherapy, Temozolomide

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

156 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Standard

Arm Type

No Intervention

Arm Description

Arm Title

Experimental arm

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Chloroquine

Other Intervention Name(s)

A-CQ

Intervention Description

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

Primary Outcome Measure Information:

Title

Six-month progression-free survival

Description

The absence of documented disease progression (clinical or radiological) or death due to any cause within six months from randomization

Time Frame

Six months after start of study treatment

Secondary Outcome Measure Information:

Title

Overall survival

Description

Randomization until death by any cause

Time Frame

2 years after start of study treatment

Title

Adverse Events (AE) and serious AEs

Description

Acute and late toxic effects are scored according to Common Toxicity Criteria for Adverse Effects (CTCAE) 4.0

Time Frame

2 years after start of study treatment

Title

Gene mutation, deletion or amplification

Description

O6-methylguanine-DNA-methyltransferase (MGMT), isocitrate dehydrogenase (IDH) and EGFRvIII in tumor tissue

Time Frame

2 years

Title

Tumor hypoxia

Description

Quantitative and qualitative assessment of [18F]HX4-PET obtained before treatment and one week after the start of CQ

Time Frame

Six months after start of study treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Inge Compter, MD

Phone

088-44556666

Inge.Compter@maastro.nl

First Name & Middle Initial & Last Name or Official Title & Degree

Danielle Eekers, MD

Phone

088-44556666

Danielle.Eekers@maastro.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Philippe Lambin, prof.

Organizational Affiliation

Maastro Clinic, The Netherlands

Official's Role

Principal Investigator

12. IPD Sharing Statement

Citations:

PubMed Identifier

16520474

Citation

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.

Results Reference

background

PubMed Identifier

23891088

Citation

Jutten 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.

Results Reference

background

PubMed Identifier

24335351

Citation

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.

Results Reference

background

PubMed Identifier

20038797

Citation

Rouschop 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 Reference

background

Learn more about this trial

The Addition of Chloroquine to Chemoradiation for Glioblastoma,

We'll reach out to this number within 24 hrs