Clinical Trial Finder

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)

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

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