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

Study Purpose

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 II 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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

  • - Histologically confirmed, newly diagnosed WHO grade II or III 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).
  • - Open biopsy or resection.
  • - Age ≥18 years.
  • - Karnofsky Performance Index (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 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) 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.
  • - Male patients are willing to use contraception.

Exclusion Criteria:

  • - Participation in other ongoing interventional clinical trials.
  • - Insufficient tumor material for molecular diagnostics.
  • - Inability to undergo MRI.
  • - Abnormal (≥ Grade 2 CTCAE v5.0) laboratory values for hematology (Hb, WBC (White Blood Cell), neutrophils, or platelets), liver (serum bilirubin, ALT (Alanine Amino Transferase), or AST (Aspartate Amino Transferase)) or renal function (serum creatinine).
  • - 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.
  • - 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.
  • - QTc (corrected QT interval) 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, Sjogren's syndrome, Guillain-Barre 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)

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT05331521
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 3
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

University Hospital Heidelberg
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Wolfgang Wick, Prof. Dr.
Principal Investigator Affiliation University Hospital Heidelberg
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other
Overall Status Recruiting
Countries Germany
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Oligodendroglioma
Additional Details

The primary objective of the NOA-18/IMPROVE CODEL trail 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.

Arms & Interventions

Arms

Active Comparator: RT PCV

Radiotherapy (RT) for over approximately 5-6 weeks: at 50.4/54 Gy in 1.8 Gy fractions for grade II and at 59.4 Gy in 1.8 Gy fractions for grade III 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).

Experimental: 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

Interventions

Drug: - CETEG

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

Drug: - PCV

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).

Radiation: - RT

Radiotherapy at 50.4/54 Gy in 1.8 Gy fractions for grade II and 59.4 Gy in 1.8 Gy fractions for grade III gliomas

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

Heidelberg, Baden-Württemberg, Germany

Status

Recruiting

Address

University Hospital Heidelberg, Department of Neurooncology

Heidelberg, Baden-Württemberg, 69120

Berlin, Germany

Status

Recruiting

Address

Charité, University Medicine Berlin, Neurosurgery

Berlin, , 10117

Bochum, Germany

Status

Recruiting

Address

Knappschaftskrankenhaus Bochum GmbH, Neurology Clinic

Bochum, , 44892

Bonn, Germany

Status

Recruiting

Address

University Hospital Bonn, Neurology Clinic

Bonn, , 53127

Chemnitz Hospital, Neurosurgery, Chemnitz, Germany

Status

Recruiting

Address

Chemnitz Hospital, Neurosurgery

Chemnitz, , 09116

Cologne, Germany

Status

Recruiting

Address

University Hospital Cologne, Neurosurgery

Cologne, , 50937

Duesseldorf, Germany

Status

Recruiting

Address

University Hospital Duesseldorf, Neurooncology

Duesseldorf, , 40225

Frankfurt, Germany

Status

Recruiting

Address

University Hospital Frankfurt, Neurooncology

Frankfurt, , 60528

Göttingen, Germany

Status

Recruiting

Address

University Hospital Göttingen, Neurosurgery

Göttingen, , 37075

Homburg, Germany

Status

Recruiting

Address

University Hospital Saarland, Neurosurgery

Homburg, , 66421

Jena, Germany

Status

Recruiting

Address

University Hospital of Jena, Neurosurgery

Jena, , 07747

Leipzig, Germany

Status

Recruiting

Address

University Hospital Leipzig, Radiation Therapy

Leipzig, , 04103

Mannheim, Germany

Status

Recruiting

Address

University Hospital Mannheim, Neurology Clinic

Mannheim, , 68167

University Clinic Muehlenkreis, Minden, Minden, Germany

Status

Recruiting

Address

University Clinic Muehlenkreis, Minden

Minden, , 32429

Munich, Germany

Status

Recruiting

Address

University Hospital rechts der Isar, Radiation Oncology

Munich, , 81675

Regensburg, Germany

Status

Recruiting

Address

University Hospital Regensburg, Neurology Clinic

Regensburg, , 93053

Helios Hospital Schwerin, Neurosurgery, Schwerin, Germany

Status

Recruiting

Address

Helios Hospital Schwerin, Neurosurgery

Schwerin, , 19049

Tuebingen, Germany

Status

Recruiting

Address

University Hospital Tuebingen, Neurooncology

Tuebingen, , 72076

Würzburg, Germany

Status

Recruiting

Address

University Hospital Wuerzburg, Neurosurgery

Würzburg, , 97080

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