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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT05331521
Registration number
NCT05331521
Ethics application status
Date submitted
15/03/2022
Date registered
15/04/2022
Date last updated
23/09/2022
Titles & IDs
Public title
A Clinical Study to Improve Brain Function and Quality of Life of Patients With Newly Diagnosed Brain Tumors (Gliomas).
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Scientific title
Improvement of Functional Outcome for Patients With Newly Diagnosed Grade II or III Glioma With Co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 Trial
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Secondary ID [1]
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2018-005027-16
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Secondary ID [2]
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NOA-18
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Universal Trial Number (UTN)
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Trial acronym
ImproveCodel
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Oligodendroglioma
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Condition category
Condition code
Cancer
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Brain
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - CETEG
Treatment: Drugs - PCV
Treatment: Other - RT
Active Comparator: RT PCV - Radiotherapy (RT) for over approximately 5-6 weeks:
at 50.4/54 Gy in 1.8 Gy fractions for grade II and
at 59.4 Gy in 1.8 Gy fractions for grade III gliomas
PCV cycles are 6 weeks long and given as:
Day 1: Lomustine (CCNU) at 110 mg/m2 body surface orally,
Days 8/29: Vincristine 1.4 mg/m2 i.v. (capped at 2 mg),
Days 8-21: Procarbazine 60 mg/m2 orally (capped at 100 mg).
Experimental: CETEG - Six 42-day cycles of lomustine plus temozolomide according to the commonly used regimen:
Day 1: Lomustine (CCNU) at 100 mg/m2
Days 2-6: Temozolomide at 100 mg/m2 (cycles 1) and in 50 mg/m2 steps to 200 mg/m2 from cycle 2 on dependent on hematological toxicity
Treatment: Drugs: CETEG
At progression, patients without prior radiotherapy will undergo radiotherapy and PCV as an adjunct chemotherapy if bone marrow reserve allows in the experimental arm.
Treatment: Drugs: PCV
In the comparator arm there is the option for second radiotherapy or even reuse of the full radiochemotherapy regimen as it had been given at diagnosis (BIC).
Treatment: Other: RT
Radiotherapy at 50.4/54 Gy in 1.8 Gy fractions for grade II and 59.4 Gy in 1.8 Gy fractions for grade III gliomas
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Intervention code [1]
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Treatment: Drugs
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Intervention code [2]
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Treatment: Other
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Qualified overall survival (qOS)
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Assessment method [1]
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The primary efficacy endpoint is the overall survival without functional and/or cognitive and/or quality of life deterioration over a period of 90 days, coined qualified overall survival (qOS). Short-term qOS is defined as the time from randomization to a deterioration in any of the following measures: NeuroCogFX®, KPI, HRQoL, NANO scale or death.
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Timepoint [1]
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From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first.
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Primary outcome [2]
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Short-term qOS deterioration in NeuroCogFX®
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Assessment method [2]
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A decline is a reduction in the mean percentile rank in 2 or more items (Fliessbach et al.
2010, Hoffermann et al. 2017) in two or more subset scores of established neuropsychometric test batteries determined by NeuroCogFX® (Fliessbach et al. 2010).
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Timepoint [2]
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Every 12 months, after a decline within 1 week and after 90 days
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Primary outcome [3]
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Short-term qOS deterioration in KPI
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Assessment method [3]
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A decrease in the KPI from 100 or 90 to 70 or less, a decrease in KPI of at least 20 from 80 or less, or a decrease in KPS from any baseline to 50 or less.
Fulfilment of one of these criteria is considered neurological deterioration unless attributable to comorbid events or changes in corticosteroid dose (van den Bent et al.
2011).
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Timepoint [3]
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From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first.
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Primary outcome [4]
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Short-term qOS deterioration in HrQoL
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Assessment method [4]
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A worsening of at least 10 points, which is the minimal clinically relevant difference, in at least one of the five selected domains of the HrQoL (global health status (GHS), physical functioning (PF), social functioning (SF), determined in the QLQ-C30 with higher scores indicate better HRQoL; communication deficits (CD) & motor dysfunction (MD) determined by QLQ-BN20 with lower scores indicate better HRQoL) (Taphoorn et al. 2015).
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Timepoint [4]
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From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first.
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Primary outcome [5]
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Short-term qOS deterioration in NANO scale
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Assessment method [5]
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A decline in the NANO scale defined as a =2 level worsening from baseline within =1 domain or worsening to the highest score within =1 domain that is felt to be related to underlying tumor progression and not attributable to a comorbid event or change in concurrent medication (Nayak et al. 2017).
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Timepoint [5]
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From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first.
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Primary outcome [6]
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Short-term qOS deterioration due to death
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Assessment method [6]
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Death due to any cause.
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Timepoint [6]
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From start of randomization until death from any cause
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Secondary outcome [1]
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Short-term qOS
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Assessment method [1]
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Defined as qOS as described above (deterioration in NeuroCogFX®, KPI, HRQoL, NANO scale or death) but neglecting the subsequent time interval of 3 months (90 days).
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Timepoint [1]
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From 3 months after start of treatment until maximum of 10 years or date of death from any cause, whichever came first.
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Secondary outcome [2]
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Overall survival (OS)
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Assessment method [2]
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Defined as the time from randomization until death due to any cause.
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Timepoint [2]
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From start of randomization until death from any cause
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Secondary outcome [3]
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Progression-free survival (PFS)
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Assessment method [3]
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Defined as the time from randomization to the day of first documentation of clinical or radiographic tumor progression or death of any cause.
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Timepoint [3]
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From randomization until the day of first documentation of clinical or radiographic tumor progression or death of any cause, whichever occurs first
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Eligibility
Key inclusion criteria
- Histologically confirmed, newly diagnosed WHO grade II or III glioma.
- Tumor carries an isocitrate dehydrogenase (IDH) mutation (determined by
immunohistochemistry (IHC) and/or deoxyribonucleic acid (DNA) sequencing).
- Tumor is co-deleted for 1p/19q (determined by copy number variations, fluorescence in
situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) or
other appropriate methods).
- Open biopsy or resection.
- Age =18 years.
- Karnofsky Performance Index (KPI) =60%.
- Life expectancy > 6 months.
- Availability of formalin-fixed paraffin-embedded (FFPE) or fresh-frozen tissue and
ethylenediamine tetraacetic acid (EDTA) blood for biomarker research.
- Standard magnetic resonance imaging (MRI) = 72 post-surgery according to the present
national and international guidelines.
- Craniotomy or intracranial biopsy site must be adequately healed.
- = 2 weeks and = 3 months from surgery without any interim radio- or chemotherapy or
experimental intervention.
- Willing and able to comply with regular neurocognitive and health-related quality of
life tests/questionnaires.
- Indication for postsurgical cytostatic/-toxic therapy.
- Written Informed consent.
- Female patients with reproductive potential have a negative pregnancy test (serum or
urine) within 6 days prior to start of therapy. Female patients are surgically sterile
or agree to use adequate contraception during the period of therapy and 6 months after
the end of study treatment, or women have been postmenopausal for at least 2 years.
- Male patients are willing to use contraception.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Participation in other ongoing interventional clinical trials.
- Insufficient tumor material for molecular diagnostics.
- Inability to undergo MRI.
- Abnormal (= Grade 2 CTCAE v5.0) laboratory values for hematology (Hb, WBC (White Blood
Cell), neutrophils, or platelets), liver (serum bilirubin, ALT (Alanine Amino
Transferase), or AST (Aspartate Amino Transferase)) or renal function (serum
creatinine).
- Active tuberculosis; known HIV infection or active Hepatitis B (HBV) or Hepatitis C
(HCV infection, or active infections requiring oral or intravenous antibiotics or that
can cause a severe disease and pose a severe danger to lab personnel working on
patients' blood or tissue (e.g. rabies).
- Any prior anti-cancer therapy or co-administration of anti-cancer therapies other than
those administered/allowed in this study. History of low-grade glioma that did not
require prior treatment with chemotherapy or radiotherapy is not an exclusion
criterion.
- Immunosuppression not related to prior treatment for malignancy.
- History of other malignancies (except for adequately treated basal or squamous cell
carcinoma or carcinoma in situ) within the last 5 years unless the patient has been
disease-free for 5 years.
- Any clinically significant concomitant disease (including hereditary fructose
intolerance) or condition that could interfere with, or for which the treatment might
interfere with, the conduct of the study or the absorption of oral medications or that
would, in the opinion of the Principal Investigator, pose an unacceptable risk to the
patient in this study.
- Any psychological, familial, sociological, or geographical condition potentially
hampering compliance with the study protocol requirements and/or follow-up procedures;
those conditions should be discussed with the patient before trial entry.
- Pregnancy or breastfeeding.
- History of hypersensitivity to the investigational medicinal product or to any drug
with similar chemical structure or to any excipient present in the pharmaceutical form
of the investigational medicinal product.
- QTc (corrected QT interval) time prolongation > 500 ms.
- Patients under restricted medication for procarbazine, lomustine, vincristine and
temozolomide.
- Liver disease characterized by:
- ALT or AST (= Grade 2 CTCAE v5.0) confirmed on two consecutive measurements OR
- Impaired excretory function (e.g., hyperbilirubinemia) or synthetic function or
other conditions of decompensated liver disease such as coagulopathy, hepatic
encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices (=
Grade 2 CTCAE v5.0) OR
- Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis
- Known uncorrected coagulopathy, platelet disorder, or history of non-drug induced
thrombocytopenia.
- History of autoimmune disease, including but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome,
multiple sclerosis, vasculitis, or glomerulonephritis; autoimmune-related
hypothyroidism (patients on a stable dose of thyroid replacement hormone are eligible
for this study) and type I diabetes mellitus (patients on a stable dose of insulin
regimen are eligible for this study).
- Vaccination with life vaccines during treatment and 4 weeks before start of treatment.
- Existing neuromuscular diseases, especially neural muscular atrophy with segmental
demyelination (demyelinising form of Charcot-Marie-Tooth syndrome)
- Chronic constipation and subileus
- Combination treatment with mitomycin (risk of a pronounced bronchospasm and acute
shortness of breath)
- Hypersensitivity to dacarbazine (DTIC)
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
7/04/2021
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
31/03/2029
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Actual
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Sample size
Target
406
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
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Recruitment outside Australia
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Germany
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Baden-Württemberg
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Germany
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Berlin
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Germany
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Bochum
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Germany
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Bonn
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Germany
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Chemnitz
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Germany
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Cologne
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Germany
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Duesseldorf
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Germany
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Frankfurt
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Germany
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Göttingen
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Germany
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Homburg
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Germany
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Jena
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Germany
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Leipzig
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Germany
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Mannheim
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Germany
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Minden
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Germany
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Munich
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Germany
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Regensburg
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Germany
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Schwerin
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Germany
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Tuebingen
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Germany
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Würzburg
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Funding & Sponsors
Primary sponsor type
Other
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Name
University Hospital Heidelberg
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Address
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Other collaborator category [1]
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Other
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Name [1]
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Universitätsmedizin Mannheim
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Other collaborator category [2]
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Other
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Ruhr University of Bochum
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Ethics approval
Ethics application status
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Summary
Brief summary
Oligodendrogliomas in the novel edition of the Central Nervous System (CNS) World Health
Organization (WHO) classification are now molecularly defined by isocitrate dehydrogenase
(IDH)1 or IDH2 mutations and 1p/19q co-deletion. The prognosis of these molecularly defined
tumors is to be determined in new series since survival data from older histology-based
studies and population-based registries are confounded by the inclusion of 20-70% not
molecularly matching subsets. Also, the optimal treatment is a matter of ongoing
investigations. An extensive, but safe surgery is associated with improved outcome as is the
addition of chemotherapy with procarbazine, CCNU (lomustine), and vincristine (PCV) to the
partial brain radiotherapy (RT). However, the exact timing of postsurgical therapy especially
for tumors of the WHO grade II and acknowledging some variability in grading as well as the
choice of chemotherapy, temozolomide instead of PCV (CODEL: NCT00887146 randomizing CNS WHO
grade 2 and 3 oligodendrogliomas to chemoradiation(CHRT)therapy with PCV or with
temozolomide) or the need for primary radiotherapy RT are subjects of clinical studies
(POLCA: NCT02444000 randomizing patients with newly diagnosed CNS WHO grade 3
oligodendrogliomas to standard CHRT with PCV or PCV alone). Given the young age of patients
with CNS WHO grade 2 and 3 oligodendrogliomas and the relevant risk of neurocognitive,
functional and quality-of-life impairment with the current aggressive standard of care
treatment, chemoradiation with PCV, of the tumor located in the brain optimizing care is the
major challenge.
NOA-18/IMPROVE CODEL aims at improving qualified overall survival (qOS) for adult patients
with CNS WHO grade 2 and 3 oligodendrogliomas by randomizing between standard chemoradiation
with up to six six-weekly cycles with PCV and six six-weekly cycles with lomustine and
temozolomide (CETEG), thereby delaying radiotherapy (RT) and adding the chemoradiotherapy
(CHRT) concept at progression after initial radiation-free chemotherapy, allowing for an
effective salvage treatment and delaying potentially deleterious side effects. QOS represents
a new concept and is defined as OS without functional and/or cognitive and/or quality of life
(QOL) deterioration regardless whether tumor progression or toxicity is the main cause.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT05331521
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Trial related presentations / publications
Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, Hawkins C, Ng HK, Pfister SM, Reifenberger G, Soffietti R, von Deimling A, Ellison DW. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021 Aug 2;23(8):1231-1251. doi: 10.1093/neuonc/noab106.
Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, Bendszus M, Balana C, Chinot O, Dirven L, French P, Hegi ME, Jakola AS, Platten M, Roth P, Ruda R, Short S, Smits M, Taphoorn MJB, von Deimling A, Westphal M, Soffietti R, Reifenberger G, Wick W. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021 Mar;18(3):170-186. doi: 10.1038/s41571-020-00447-z. Epub 2020 Dec 8. Erratum In: Nat Rev Clin Oncol. 2022 May;19(5):357-358.
Fliessbach K, Rogowski S, Hoppe C, Sabel M, Goeppert M, Helmstaedter C, Calabrese P, Schackert G, Tonn JC, Simon M, Schlegel U. Computer-based assessment of cognitive functions in brain tumor patients. J Neurooncol. 2010 Dec;100(3):427-37. doi: 10.1007/s11060-010-0194-9. Epub 2010 May 7.
Hoffermann M, Bruckmann L, Mahdy Ali K, Zaar K, Avian A, von Campe G. Pre- and postoperative neurocognitive deficits in brain tumor patients assessed by a computer based screening test. J Clin Neurosci. 2017 Feb;36:31-36. doi: 10.1016/j.jocn.2016.10.030. Epub 2016 Nov 9.
Taphoorn MJ, Henriksson R, Bottomley A, Cloughesy T, Wick W, Mason WP, Saran F, Nishikawa R, Hilton M, Theodore-Oklota C, Ravelo A, Chinot OL. Health-Related Quality of Life in a Randomized Phase III Study of Bevacizumab, Temozolomide, and Radiotherapy in Newly Diagnosed Glioblastoma. J Clin Oncol. 2015 Jul 1;33(19):2166-75. doi: 10.1200/JCO.2014.60.3217. Epub 2015 May 26.
Nayak L, DeAngelis LM, Brandes AA, Peereboom DM, Galanis E, Lin NU, Soffietti R, Macdonald DR, Chamberlain M, Perry J, Jaeckle K, Mehta M, Stupp R, Muzikansky A, Pentsova E, Cloughesy T, Iwamoto FM, Tonn JC, Vogelbaum MA, Wen PY, van den Bent MJ, Reardon DA. The Neurologic Assessment in Neuro-Oncology (NANO) scale: a tool to assess neurologic function for integration into the Response Assessment in Neuro-Oncology (RANO) criteria. Neuro Oncol. 2017 May 1;19(5):625-635. doi: 10.1093/neuonc/nox029.
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010 Apr 10;28(11):1963-72. doi: 10.1200/JCO.2009.26.3541. Epub 2010 Mar 15.
Wick W, Roth P, Hartmann C, Hau P, Nakamura M, Stockhammer F, Sabel MC, Wick A, Koeppen S, Ketter R, Vajkoczy P, Eyupoglu I, Kalff R, Pietsch T, Happold C, Galldiks N, Schmidt-Graf F, Bamberg M, Reifenberger G, Platten M, von Deimling A, Meisner C, Wiestler B, Weller M; Neurooncology Working Group (NOA) of the German Cancer Society. Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. Neuro Oncol. 2016 Nov;18(11):1529-1537. doi: 10.1093/neuonc/now133. Epub 2016 Jul 1. Erratum In: Neuro Oncol. 2016 Nov;18(11):e1.
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Contacts
Principal investigator
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Wolfgang Wick, Prof. Dr.
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University Hospital Heidelberg
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Contact person for public queries
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Wolfgang Wick, Prof. Dr.
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+49 6221 56
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[email protected]
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT05331521
Download to PDF