A Clinical Study to Improve Brain Function and Quality of Life of Patients With Newly Diagnosed Brain Tumors (Gliomas).
NCT ID: NCT05331521
Last Updated: 2026-02-03
Study Results
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Basic Information
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RECRUITING
PHASE3
406 participants
INTERVENTIONAL
2021-04-07
2033-03-31
Brief Summary
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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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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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RT PCV
Radiotherapy (RT) for over approximately 5-6 weeks:
* at 50.4/54 Gy in 1.8 Gy fractions for grade 2 and
* at 59.4 Gy in 1.8 Gy fractions for grade 3 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).
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).
RT
Radiotherapy at 50.4/54 Gy in 1.8 Gy fractions for grade 2 and 59.4 Gy in 1.8 Gy fractions for grade 3 gliomas
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
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.
Interventions
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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.
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).
RT
Radiotherapy at 50.4/54 Gy in 1.8 Gy fractions for grade 2 and 59.4 Gy in 1.8 Gy fractions for grade 3 gliomas
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Tumor carries an isocitrate dehydrogenase (IDH) mutation (determined by immunohistochemistry (IHC) and/or deoxyribonucleic acid (DNA) sequencing).
3. 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).
4. Biopsy (with sufficient tissue for molecular pathology) or resection.
5. Age: ≥18 years.
6. Karnofsky Performance status (KPI) ≥60%.
7. Life expectancy \>6 months.
8. Availability of formalin-fixed paraffin-embedded (FFPE) or fresh-frozen tissue and ethylenediamine tetraacetic acid (EDTA) blood for biomarker research.
9. Standard magnetic resonance imaging (MRI) ≤ 72 h post-surgery according to the present national and international guidelines.
10. Craniotomy or intracranial biopsy site must be adequately healed.
11. ≥ 2 weeks and ≤ 3 months from surgery without any interim radio- or chemotherapy or experimental intervention.
12. Willing and able to comply with regular neurocognitive and health-related quality of life tests/questionnaires.
13. Indication for postsurgical cytostatic/-toxic therapy.
14. Written Informed consent.
15. Female patients with reproductive potential have a negative pregnancy test (serum or urine) day -6 until day 0 of screening (and 3 days prior to first IMP-intake or RT). Female patients are surgically sterile or agree to use adequate contraception during the period of therapy and 7 months after the end of study treatment, or women have been postmenopausal for at least 2 years.
16. Male patients are willing to use contraception
Exclusion Criteria
2. Inability to undergo MRI.
3. Abnormal (≥ Grade 2 CTCAE v5.0 laboratory values for hematology (Hb, WBC, neutrophils, or platelets), liver (serum bilirubin, ALT, or AST) or renal function (serum creatinine).
4. Clinically 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).
5. 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.
6. Immunosuppression, not related to prior treatment for malignancy.
7. 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.
8. 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.
9. 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.
10. Pregnancy or breastfeeding.
11. 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. (E.g.: In the discretion of the investigator patients are allowed to take part in the study even if they suffer from celiac disease: Cecenu contains very small amounts of gluten (from wheat starch). It is considered gluten-free and is tolerated by patients suffering from celiac disease. One capsule contains no more than 4 micrograms of Gluten.)
12. QTc time prolongation \>500 ms.
13. Patients under restricted medication for procarbazine, lomustine, vincristine and temozolomide.
14. Liver disease characterized by:
1. ALT or AST (≥ Grade 2 CTCAE v5.0) confirmed on two consecutive measurements OR
2. 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
3. Acute viral or active autoimmune, alcoholic, or other types of acute hepatitis.
15. Known uncorrected coagulopathy, platelet disorder, or history of non-drug induced thrombocytopenia.
16. 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, Sjögren's syndrome, Guillain-Barré 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).
17. Vaccination with life vaccines during treatment and 4 weeks before start of treatment.
18. Existing neuromuscular diseases, especially neural muscular atrophy with segmental demyelination (demyelinising form of Charcot-Marie-Tooth syndrome).
19. Chronic constipation and subileus.
20. Combination treatment with mitomycin (risk of a pronounced bronchospasm and acute shortness of breath).
21. Hypersensitivity to dacarbazine (DTIC).
22. Patients with hereditary galactose intolerance, complete lactase deficiency or glucose-galactose malabsorption (Temodal contains Lactose).
23. Patients with clinical wheat allergy.
18 Years
ALL
No
Sponsors
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Universitätsmedizin Mannheim
OTHER
Ruhr University of Bochum
OTHER
University Hospital Heidelberg
OTHER
Responsible Party
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Prof. Dr. Wolfgang Wick
Medical Director of Neurology
Principal Investigators
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Wolfgang Wick, Prof. Dr.
Role: PRINCIPAL_INVESTIGATOR
University Hospital Heidelberg
Locations
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University Hospital Heidelberg, Department of Neurooncology
Heidelberg, Baden-Wurttemberg, Germany
Charité, University Medicine Berlin, Neurosurgery
Berlin, , Germany
Knappschaftskrankenhaus Bochum GmbH, Neurology Clinic
Bochum, , Germany
University Hospital Bonn, Neurology Clinic
Bonn, , Germany
Chemnitz Hospital, Neurosurgery
Chemnitz, , Germany
University Hospital Cologne, Neurosurgery
Cologne, , Germany
University Hospital Duesseldorf, Neurooncology
Düsseldorf, , Germany
University Hospital Frankfurt, Neurooncology
Frankfurt, , Germany
University Hospital Göttingen, Neurosurgery
Göttingen, , Germany
University Hospital Saarland, Neurosurgery
Homburg, , Germany
University Hospital of Jena, Neurosurgery
Jena, , Germany
University Hospital Leipzig, Radiation Therapy
Leipzig, , Germany
University Hospital Mannheim, Neurology Clinic
Mannheim, , Germany
University Clinic Muehlenkreis, Minden
Minden, , Germany
University Hospital rechts der Isar, Radiation Oncology
Munich, , Germany
University Hospital Regensburg, Neurology Clinic
Regensburg, , Germany
Helios Hospital Schwerin, Neurosurgery
Schwerin, , Germany
University Hospital Tuebingen, Neurooncology
Tübingen, , Germany
University Hospital Wuerzburg, Neurosurgery
Würzburg, , Germany
Countries
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Central Contacts
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References
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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.
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.
Wick A, Sander A, Koch M, Bendszus M, Combs S, Haut T, Dormann A, Walter S, Pertz M, Merkle-Lock J, Selkrig N, Limprecht R, Baumann L, Kieser M, Sahm F, Schlegel U, Winkler F, Platten M, Wick W, Kessler T. Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial. BMC Cancer. 2022 Jun 13;22(1):645. doi: 10.1186/s12885-022-09720-z.
Other Identifiers
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2018-005027-16
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
2024-510616-73-00
Identifier Type: CTIS
Identifier Source: secondary_id
NOA-18
Identifier Type: -
Identifier Source: org_study_id
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