A Clinical Study to Improve Brain Function and Quality of Life of Patients With Newly Diagnosed Brain Tumors (Gliomas).

NCT05331521 | Recruiting Phase 3 DMC

• 3 other identifiers: NOA-182018-005027-162024-510616-73-00
• Study Type: interventional
• Target: 406
• Locations: 1 country
• Sites: 19

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 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.

Conditions

Oligodendroglioma

Keywords

Radiotherapy; Chemotherapy; Temozolomide

Outcome Measures

Primary Outcomes (6)

• 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).

  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

  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.

  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).

  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.

  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.

  From start of randomization until death from any cause till the end of follow up at 120 months.

Secondary Outcomes (3)

• Short-term qOS

  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)

  From start of randomization until death from any cause till the end of follow up at 120 months.

• Progression-free survival (PFS)

  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.

Study Arms (2)

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).

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

Drug: CETEG

Interventions

CETEG DRUG

At progression, patients without prior radiotherapy will undergo radiotherapy and PCV as an adjunct chemotherapy if bone marrow reserve allows in the experimental arm.

Also known as: Lomustine (CCNU) and Temozolomide

CETEG

PCV DRUG

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).

Also known as: Procarbazine, Lomustine and Vincristine

RT PCV

RT RADIATION

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

Also known as: Radiotherapy

RT PCV

Eligibility Criteria

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

You may qualify if:

• 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%.
• 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.

You may not qualify if:

• 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).
• 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. (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

Sponsors & Collaborators

• University Hospital Heidelberg: lead
• Universitätsmedizin Mannheim: collaborator
• Ruhr University of Bochum: collaborator

Study Sites (19)

University Hospital Heidelberg, Department of Neurooncology

Heidelberg, Baden-Wurttemberg, 69120, Germany

RECRUITING

Charité, University Medicine Berlin, Neurosurgery

Berlin, 10117, Germany

RECRUITING

Knappschaftskrankenhaus Bochum GmbH, Neurology Clinic

Bochum, 44892, Germany

RECRUITING

University Hospital Bonn, Neurology Clinic

Bonn, 53127, Germany

RECRUITING

Chemnitz Hospital, Neurosurgery

Chemnitz, 09116, Germany

RECRUITING

University Hospital Cologne, Neurosurgery

Cologne, 50937, Germany

RECRUITING

University Hospital Duesseldorf, Neurooncology

Düsseldorf, 40225, Germany

RECRUITING

University Hospital Frankfurt, Neurooncology

Frankfurt, 60528, Germany

RECRUITING

University Hospital Göttingen, Neurosurgery

Göttingen, 37075, Germany

RECRUITING

University Hospital Saarland, Neurosurgery

Homburg, 66421, Germany

RECRUITING

University Hospital of Jena, Neurosurgery

Jena, 07747, Germany

RECRUITING

University Hospital Leipzig, Radiation Therapy

Leipzig, 04103, Germany

RECRUITING

University Hospital Mannheim, Neurology Clinic

Mannheim, 68167, Germany

RECRUITING

University Clinic Muehlenkreis, Minden

Minden, 32429, Germany

RECRUITING

University Hospital rechts der Isar, Radiation Oncology

Munich, 81675, Germany

RECRUITING

University Hospital Regensburg, Neurology Clinic

Regensburg, 93053, Germany

RECRUITING

Helios Hospital Schwerin, Neurosurgery

Schwerin, 19049, Germany

RECRUITING

University Hospital Tuebingen, Neurooncology

Tübingen, 72076, Germany

RECRUITING

University Hospital Wuerzburg, Neurosurgery

Würzburg, 97080, Germany

RECRUITING

Related Publications (9)

• 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.

  PMID: 34185076 BACKGROUND

• 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.

  PMID: 33293629 BACKGROUND

• 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.

  PMID: 20449630 BACKGROUND

• 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.

  PMID: 27836394 BACKGROUND

• 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.

  PMID: 26014298 BACKGROUND

• 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.

  PMID: 28453751 BACKGROUND

• 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.

  PMID: 20231676 BACKGROUND

• 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.

  PMID: 27370396 BACKGROUND

• 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.

  PMID: 35692047 DERIVED

MeSH Terms

Conditions

Oligodendroglioma

Interventions

Lomustine; Temozolomide; Procarbazine; Vincristine; Radiotherapy

Condition Hierarchy (Ancestors)

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)

Nitrosourea Compounds; Urea; Amides; Organic Chemicals; Nitroso Compounds; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzamides; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Therapeutics

Study Officials

• Wolfgang Wick, Prof. Dr.

  University Hospital Heidelberg

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Wolfgang Wick, Prof. Dr.

CONTACT

+49 6221 56; wolfgang.wick@med.uni-heidelberg.de

Antje Wick, PD Dr.

CONTACT

+49 6221 56; antje.wick@med.uni-heidelberg.de

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Director of Neurology

Study Record Dates

• First Submitted: March 15, 2022
• First Posted: April 15, 2022
• Study Start: April 7, 2021
• Primary Completion (Estimated): March 31, 2033
• Study Completion (Estimated): March 31, 2033
• Last Updated: February 3, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

DE (19)