The Addition of Chloroquine to Chemoradiation for Glioblastoma

NCT02378532 | Completed Phase 1 DMC

• 1 other identifier: CHLOROBRAIN
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Glioblastoma Multiforme

Keywords

Glioblastoma; Chloroquine; Autophagy; EGFRvIII; Radiotherapy; Temozolomide

Outcome Measures

Primary Outcomes (1)

• Toxicity (CTC AE 4.0

  Determining the MTD of chloroquine as a radiosensitizer

  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.

  up to 2 years

• Presence of autophagic markers (LC3 and autophagic vesicles)

  up to 2 years

• Evaluation of EGFRvIII status in histopathological material

  up to 2 years

Study Arms (1)

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.

Drug: Chloroquine; Radiation: Radiotherapy; Drug: Temozolomide

Interventions

Chloroquine DRUG

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.

Radiotherapy/Temozolomide + Chloroquine

Radiotherapy RADIATION

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.

Radiotherapy/Temozolomide + Chloroquine

Temozolomide DRUG

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.

Also known as: Temodal

Radiotherapy/Temozolomide + Chloroquine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• years or older
• Karnofsky performance status ≥ 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Maastricht Radiation Oncology: lead

Study Sites (1)

Maastricht Radiation Oncology

Maastricht, 6202 AZ, Netherlands

Location

Related Publications (4)

• 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.

  PMID: 24335351 BACKGROUND

• 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.

  PMID: 20038797 BACKGROUND

• 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.

  PMID: 16520474 RESULT

• 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.

  PMID: 23891088 RESULT

MeSH Terms

Conditions

Glioblastoma

Interventions

Chloroquine; Radiotherapy; Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Therapeutics; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Dirk De Ruysscher, prof.

  Maastro Clinic, The Netherlands

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2015
• First Posted: March 4, 2015
• Study Start: August 1, 2016
• Primary Completion: January 17, 2019
• Study Completion: July 30, 2019
• Last Updated: January 23, 2020

Record last verified: 2020-01

Locations

NL (1)