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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
406
At progression, patients without prior radiotherapy will undergo radiotherapy and PCV as an adjunct chemotherapy if bone marrow reserve allows in the experimental arm.
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).
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
University Hospital Heidelberg, Department of Neurooncology
Heidelberg, Baden-Wurttemberg, Germany
RECRUITINGCharité, University Medicine Berlin, Neurosurgery
Berlin, Germany
RECRUITINGKnappschaftskrankenhaus Bochum GmbH, Neurology Clinic
Bochum, Germany
RECRUITINGUniversity Hospital Bonn, Neurology Clinic
Bonn, Germany
RECRUITINGChemnitz Hospital, Neurosurgery
Chemnitz, Germany
RECRUITINGUniversity Hospital Cologne, Neurosurgery
Cologne, Germany
RECRUITINGUniversity Hospital Duesseldorf, Neurooncology
Düsseldorf, Germany
RECRUITINGUniversity Hospital Frankfurt, Neurooncology
Frankfurt, Germany
RECRUITINGUniversity Hospital Göttingen, Neurosurgery
Göttingen, Germany
RECRUITINGUniversity Hospital Saarland, Neurosurgery
Homburg, Germany
RECRUITING...and 9 more locations
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).
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.
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
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.
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.
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.
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).
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.
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.
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.
Short-term qOS deterioration due to death
Death due to any cause.
Time frame: From start of randomization until death from any cause till the end of follow up at 120 months.
Short-term qOS
Defined qOS defined as qOS as described above, but neglecting the subsequent time interval of 3 months (90 days).
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)
Defined as the time from randomization until death due to any cause.
Time frame: 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.
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.
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