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.
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.
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).
Parallel
CETEG
DrugAt progression, patients without prior radiotherapy will undergo radiotherapy and PCV as an adjunct chemotherapy if bone marrow reserve allows in the experimental arm.
PCV
DrugIn 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
RadiationRadiotherapy 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
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).
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
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.
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).
Short-term qOS
Defined qOS defined as qOS as described above, but neglecting the subsequent time interval of 3 months (90 days).
Overall survival (OS)
Defined as the time from randomization until death due to any cause.
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.
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University Hospital Heidelberg
Lead sponsor
Universitätsmedizin Mannheim
Collaborator
Ruhr University of Bochum
Collaborator
