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

Phase 3

Recruiting

• Conditions: Oligodendroglioma
• Interventions: Drug: PCV; Drug: CETEG; Radiation: RT

• Registration Number: NCT05331521
• Lead Sponsor: University Hospital Heidelberg

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.

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 Timeline

• Study Start: 2021-04-07
• Study First Submitted: 2022-03-15
• Study First Submitted QC: 2022-04-11
• Study First Posted: 2022-04-15
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-17
• Last Update Posted: 2025-01-22
• Primary Completion: 2031-03-31
• Study Completion: 2031-03-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 406

Inclusion Criteria

1. Histologically confirmed, newly diagnosed CNS WHO grade 2 or 3 glioma.
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) within 6 days prior to start of therapy. Female patients are surgically sterile or agree to use adequate contraception during the period of therapy and 6 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

1. Participation in other ongoing interventional clinical trials.

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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RT PCV	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).
RT PCV	RT	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).
CETEG	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

Primary Outcome Measures

Name	Time	Method
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.	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®	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	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	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	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	From start of randomization until death from any cause till the end of follow up at 120 months.	Death due to any cause.

Secondary Outcome Measures

Name	Time	Method
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.	Defined qOS defined as qOS as described above, but neglecting the subsequent time interval of 3 months (90 days).
Overall survival (OS)	From start of randomization until death from any cause till the end of follow up at 120 months.	Defined as the time from randomization until death due to any cause.
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.	Defined as the time from randomization to the day of first documentation of clinical or radiographic tumor progression or death of any cause.

Trial Locations

Locations (19)

University Hospital Cologne, Neurosurgery; 🇩🇪 Cologne, Germany

University Hospital Leipzig, Radiation Therapy; 🇩🇪 Leipzig, Germany

Helios Hospital Schwerin, Neurosurgery; 🇩🇪 Schwerin, Germany

University Hospital Tuebingen, Neurooncology; 🇩🇪 Tuebingen, Germany

University Hospital Frankfurt, Neurooncology; 🇩🇪 Frankfurt, Germany

University Hospital rechts der Isar, Radiation Oncology; 🇩🇪 Munich, Germany

University Hospital of Jena, Neurosurgery; 🇩🇪 Jena, Germany

University Hospital Saarland, Neurosurgery; 🇩🇪 Homburg, Germany

University Hospital Bonn, Neurology Clinic; 🇩🇪 Bonn, Germany

University Hospital Göttingen, Neurosurgery; 🇩🇪 Göttingen, Germany

University Hospital Heidelberg, Department of Neurooncology; 🇩🇪 Heidelberg, Baden-Württemberg, Germany

Knappschaftskrankenhaus Bochum GmbH, Neurology Clinic; 🇩🇪 Bochum, Germany

Chemnitz Hospital, Neurosurgery; 🇩🇪 Chemnitz, Germany

University Hospital Duesseldorf, Neurooncology; 🇩🇪 Duesseldorf, Germany

University Hospital Mannheim, Neurology Clinic; 🇩🇪 Mannheim, Germany

University Clinic Muehlenkreis, Minden; 🇩🇪 Minden, Germany

University Hospital Regensburg, Neurology Clinic; 🇩🇪 Regensburg, Germany

University Hospital Wuerzburg, Neurosurgery; 🇩🇪 Würzburg, Germany

Charité, University Medicine Berlin, Neurosurgery; 🇩🇪 Berlin, Germany