OligodendrogliomaPhase 3ImproveCodelNCT05331521
A Clinical Study to Improve Brain Function and Quality of Life of Patients With Newly Diagnosed Brain Tumors (Gliomas).
A Phase 3 study testing CETEG, PCV and RT in people with Oligodendroglioma, run by University Hospital Heidelberg at 19 sites in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Oligodendroglioma
- What is being tested?
- CETEG, PCV and RT
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 406 participants
- Where
- 19 sitesGermany
- Study dates
- 7 Apr 2021to 31 Mar 2033
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed, newly diagnosed CNS WHO grade 2 or 3 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).
- Biopsy (with sufficient tissue for molecular pathology) or resection.
- Age: ≥18 years.
- Karnofsky Performance status (KPI) ≥60%.
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- 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 h 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) 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.
- Male patients are willing to use contraception
Who cannot join
- Participation in other ongoing interventional clinical trials.
- Inability to undergo MRI.
- 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).
- 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).
- 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.
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- 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. (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.)
- QTc 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, 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).
- 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).
- Patients with hereditary galactose intolerance, complete lactase deficiency or glucose-galactose malabsorption (Temodal contains Lactose).
- Patients with clinical wheat allergy.
Trial locations and contacts
19 sites in 1 country. Contact the study team or a site near you to ask about taking part.
19 sites in 1 country
Germany19 sites, 19 recruiting
- Recruiting
Charité, University Medicine Berlin, Neurosurgery
Berlin, 10117
- Recruiting
Knappschaftskrankenhaus Bochum GmbH, Neurology Clinic
Bochum, 44892
- Recruiting
University Hospital Bonn, Neurology Clinic
Bonn, 53127
- Recruiting
Chemnitz Hospital, Neurosurgery
Chemnitz, 09116
- Recruiting
University Hospital Cologne, Neurosurgery
Cologne, 50937
- Recruiting
University Hospital Duesseldorf, Neurooncology
Düsseldorf, 40225
- Recruiting
University Hospital Frankfurt, Neurooncology
Frankfurt, 60528
- Recruiting
University Hospital Göttingen, Neurosurgery
Göttingen, 37075
- Recruiting
University Hospital Heidelberg, Department of Neurooncology
Heidelberg, Baden-Wurttemberg, 69120
Wolfgang Wick, Prof. Dr.
- Recruiting
University Hospital Saarland, Neurosurgery
Homburg, 66421
- Recruiting
University Hospital of Jena, Neurosurgery
Jena, 07747
- Recruiting
University Hospital Leipzig, Radiation Therapy
Leipzig, 04103
- Recruiting
University Hospital Mannheim, Neurology Clinic
Mannheim, 68167
- Recruiting
University Clinic Muehlenkreis, Minden
Minden, 32429
- Recruiting
University Hospital rechts der Isar, Radiation Oncology
Munich, 81675
- Recruiting
University Hospital Regensburg, Neurology Clinic
Regensburg, 93053
- Recruiting
Helios Hospital Schwerin, Neurosurgery
Schwerin, 19049
- Recruiting
University Hospital Tuebingen, Neurooncology
Tübingen, 72076
- Recruiting
University Hospital Wuerzburg, Neurosurgery
Würzburg, 97080
About this study
Official title: Improvement of Functional Outcome for Patients With Newly Diagnosed Grade 2 or 3 Glioma With Co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 Trial
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 2 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.
Read the detailed description
The primary objective of the NOA-18/IMPROVE CODEL trial is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event with respect to a sustained qOS is then defined as a functional and/or cognitive deterioration on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with 3-monthly MRI, assessment of the NANO (Neurologic assessment in neuro-oncology) scale, HRQoL, and KPS (Karnofsky performance status) and annually cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at 21 NOA (Neurooncology Working Party of the German Cancer Society) study sites in Germany.
- Conditions
- Oligodendroglioma
- Being tested
- CETEG, PCV, RT
- Keywords
- Radiotherapy, Chemotherapy, Temozolomide
- Medical subject headings
- Oligodendroglioma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CETEGDrug
Also called Lomustine (CCNU) and Temozolomide
At progression, patients without prior radiotherapy will undergo radiotherapy and PCV as an adjunct chemotherapy if bone marrow reserve allows in the experimental arm.
PCVDrug
Also called Procarbazine, Lomustine and Vincristine
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).
RTRadiation
Also called Radiotherapy
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
| Study group | Role | What they receive |
|---|---|---|
| RT PCV | Active comparator | 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). Receives: Drug: PCV; Radiation: RT |
| CETEG | Experimental | 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 Receives: Drug: CETEG |
What is being measured
The primary outcome is the main question the study is designed to answer.
Qualified overall survival (qOS)
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).
Measured: Counted as event starting 12 months (365 days) after randomization on 2 consecutive study visits with an interval of 3 months (90 days) till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
Short-term qOS deterioration in NeuroCogFX®
The primary efficacy endpoint is 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 detriment of ≥ 1.5 standard deviations below the normative mean (i.e. percentile rank ≤ 6.68) in two or more NeuroCog FX® subtests AND Related to baseline: 90%-confidence intervals of NeuroCog FX® subtests indicate a clinically and statistically meaningful individual change (i.e. deterioration) in two or more NeuroCog FX® subtest raw scores
Measured: Counted as event starting 12 months (365 days) after randomization on 2 consecutive study visits with an interval of 3 months (90 days) till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
Short-term qOS deterioration in KPI
The primary efficacy endpoint is 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 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 KPI 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.
Measured: Counted as event starting 12 months (365 days) after randomization on 2 consecutive study visits with an interval of 3 months (90 days) till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
Short-term qOS deterioration in HrQoL
The primary efficacy endpoint is 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 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).
Measured: Counted as event starting 12 months (365 days) after randomization on 2 consecutive study visits with an interval of 3 months (90 days) till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
Short-term qOS deterioration in NANO scale
The primary efficacy endpoint is 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 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.
Measured: Counted as event starting 12 months (365 days) after randomization on 2 consecutive study visits with an interval of 3 months (90 days) till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
Short-term qOS deterioration due to death
Death due to any cause.
Measured: From start of randomization until death from any cause till the end of follow up at 120 months.
Secondary outcomes (3)
Short-term qOS
Defined qOS defined as qOS as described above, but neglecting the subsequent time interval of 3 months (90 days).
Measured: From 3 months after start of treatment, every 3 months till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
Overall survival (OS)
Defined as the time from randomization until death due to any cause.
Measured: From start of randomization until death from any cause till the end of follow up at 120 months.
Progression-free survival (PFS)
Defined as the time from randomization to the day of first documentation of clinical or radiographic tumor progression or death of any cause.
Measured: From randomization until the day of first documentation of clinical or radiographic tumor progression or death of any cause till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Apr 2022
- Study start7 Apr 2021
- Primary completion31 Mar 2033 (estimated)
- Study completion31 Mar 2033 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for OligodendrogliomaStudies of the same condition, open and under way.
- More trials run by University Hospital HeidelbergThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 406 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital Heidelberg
- Sponsor type
- University, hospital or other
- Collaborators
- Universitätsmedizin Mannheim, Ruhr University of Bochum
- Responsible party
- Principal investigator, Prof. Dr. Wolfgang Wick, University Hospital Heidelberg
- Investigators
- Wolfgang Wick, Prof. Dr., Principal investigator, University Hospital Heidelberg
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05331521
- Sponsor's protocol ID
- NOA-18
- Other IDs
- 2018-005027-16, 2024-510616-73-00, 2018
- Acronym
- ImproveCodel
- Status last verified
- Jan 2026
- First submitted
- 15 Mar 2022
- Last updated
- 3 Feb 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 34185076Weller 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.
PubMed 33293629Fliessbach 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.
PubMed 20449630Hoffermann 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.
PubMed 27836394Taphoorn 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.
PubMed 26014298Nayak 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.
PubMed 28453751Wen 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.
PubMed 20231676Wick 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.
PubMed 27370396Wick 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.
PubMed 35692047
Study at a glance
From the registry record, last updated by the sponsor on 3 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Improvement of Functional Outcome for Patients With Newly Diagnosed Grade 2 or 3 Glioma With Co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 Trial
- ClinicalTrials.gov ID
- NCT05331521
- Acronym / sponsor ID
- ImproveCodel / NOA-18
- Conditions
- Oligodendroglioma
- Keywords
- Radiotherapy, Chemotherapy, Temozolomide
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 406 participants (estimated)
- Lead sponsor
- University Hospital HeidelbergUniversity, hospital or other
- Collaborators
- Universitätsmedizin Mannheim, Ruhr University of Bochum
- Study start
- 7 Apr 2021 (actual)
- Primary completion
- 31 Mar 2033 (estimated)
- Study completion
- 31 Mar 2033 (estimated)
- First posted
- 15 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 2 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.
Detailed description
The primary objective of the NOA-18/IMPROVE CODEL trial is to show superiority of an initial CETEG treatment followed by partial brain radiotherapy (RT) plus PCV (RT-PCV) at progression over partial brain radiotherapy (RT) followed by procarbazine, lomustine and vincristine (PCV) chemotherapy (RT-PCV) and best investigators choice (BIC) at progression for sustained qOS. An event with respect to a sustained qOS is then defined as a functional and/or cognitive deterioration on two consecutive study visits with an interval of 3 months, tolerating a deviation of at most 1 month. Assessments are done with 3-monthly MRI, assessment of the NANO (Neurologic assessment in neuro-oncology) scale, HRQoL, and KPS (Karnofsky performance status) and annually cognitive testing. Secondary objectives are evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate). The trial is planned to be conducted at 21 NOA (Neurooncology Working Party of the German Cancer Society) study sites in Germany.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| RT PCV | Active comparator | Drug: PCV, Radiation: RTRadiotherapy (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). |
| CETEG | Experimental | Drug: CETEGSix 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Histologically confirmed, newly diagnosed CNS WHO grade 2 or 3 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).
- Biopsy (with sufficient tissue for molecular pathology) or resection.
- Age: ≥18 years.
Key exclusion criteria (26 listed)
- Participation in other ongoing interventional clinical trials.
- Inability to undergo MRI.
- 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).
- 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).
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CETEGAlso: Lomustine (CCNU) and TemozolomideAt progression, patients without prior radiotherapy will undergo radiotherapy and PCV as an adjunct chemotherapy if bone marrow reserve allows in the experimental arm. | Drug | CETEG |
| PCVAlso: Procarbazine, Lomustine and VincristineIn 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). | Drug | RT PCV |
| RTAlso: RadiotherapyRadiotherapy 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 | Radiation | RT PCV |
Primary outcome
Qualified overall survival (qOS)
Time frame: Counted as event starting 12 months (365 days) after randomization on 2 consecutive study visits with an interval of 3 months (90 days) till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
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 deterioration in NeuroCogFX®
Time frame: Counted as event starting 12 months (365 days) after randomization on 2 consecutive study visits with an interval of 3 months (90 days) till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
The primary efficacy endpoint is 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 detriment of ≥ 1.5 standard deviations below the normative mean (i.e. percentile rank ≤ 6.68) in two or more NeuroCog FX® subtests AND Related to baseline: 90%-confidence intervals of NeuroCog FX® subtests indicate a clinically and statistically meaningful individual change (i.e. deterioration) in two or more NeuroCog FX® subtest raw scores
Short-term qOS deterioration in KPI
Time frame: Counted as event starting 12 months (365 days) after randomization on 2 consecutive study visits with an interval of 3 months (90 days) till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
The primary efficacy endpoint is 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 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 KPI 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.
Short-term qOS deterioration in HrQoL
Time frame: Counted as event starting 12 months (365 days) after randomization on 2 consecutive study visits with an interval of 3 months (90 days) till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
The primary efficacy endpoint is 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 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).
Short-term qOS deterioration in NANO scale
Time frame: Counted as event starting 12 months (365 days) after randomization on 2 consecutive study visits with an interval of 3 months (90 days) till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
The primary efficacy endpoint is 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 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.
Short-term qOS deterioration due to death
Time frame: From start of randomization until death from any cause till the end of follow up at 120 months.
Death due to any cause.
3 secondary outcomes
Short-term qOS
Time frame: From 3 months after start of treatment, every 3 months till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
Overall survival (OS)
Time frame: From start of randomization until death from any cause till the end of follow up at 120 months.
Progression-free survival (PFS)
Time frame: From randomization until the day of first documentation of clinical or radiographic tumor progression or death of any cause till the end of follow up at 120 months or date of death from any cause, whatever occurs first.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Feb 2026.
- Background: PubMed 34185076Louis 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.
- Background: PubMed 33293629Weller 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.
- Background: PubMed 20449630Fliessbach 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.
- Background: PubMed 27836394Hoffermann 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.
- Background: PubMed 26014298Taphoorn 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.
- Background: PubMed 28453751Nayak 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.
- Background: PubMed 20231676Wen 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.
- Background: PubMed 27370396Wick 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.
- Derived from this study: PubMed 35692047Wick 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Wolfgang Wick, Prof. Dr. principal investigator
University Hospital Heidelberg
19 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing CETEG, PCV and RT in people with Oligodendroglioma, run by University Hospital Heidelberg at 19 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 3 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 19 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Wolfgang Wick, Prof. Dr. (+49 6221 56 ext. 7075, wolfgang.wick@med.uni-heidelberg.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Qualified overall survival (qOS) (time frame: Counted as event starting 12 months (365 days) after randomization on 2 consecutive study visits with an interval of 3 months (90 days) till the end of follow up at 120 months or date of death from any cause, whatever occurs first.). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05331521, which also lists 9 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Feb 2026.