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

Study Overview
=================
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 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.

Detailed Description
-----------------
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.

Official Title
-----------------
Improvement of Functional Outcome for Patients With Newly Diagnosed Grade II or III Glioma With Co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 Trial

Conditions
-----------------
Oligodendroglioma

Intervention / Treatment
-----------------
* Drug: CETEG
* Drug: PCV
* Radiation: RT


Participation Criteria
=================
Eligibility 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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RT PCV<br>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). | Drug: PCV<br>* 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).<br>* Other names: Procarbazine, Lomustine and Vincristine;Radiation: RT<br>* 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<br>* Other names: Radiotherapy;|
| Experimental: CETEG<br>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 | Drug: CETEG<br>* At progression, patients without prior radiotherapy will undergo radiotherapy and PCV as an adjunct chemotherapy if bone marrow reserve allows in the experimental arm.<br>* Other names: Lomustine (CCNU) and Temozolomide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 is defined as the time from randomization to a deterioration in any of the following measures: NeuroCogFX®, KPI, HRQoL, NANO scale or death. | From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first. | 
| Short-term qOS deterioration in NeuroCogFX® | A decline is a reduction in the mean percentile rank in 2 or more items (Fliessbach et al. 2010, Hoffermann et al. 2017) in two or more subset scores of established neuropsychometric test batteries determined by NeuroCogFX® (Fliessbach et al. 2010). | Every 12 months, after a decline within 1 week and after 90 days | 
| Short-term qOS deterioration in KPI | 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 KPS 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 (van den Bent et al. 2011). | From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first. | 
| Short-term qOS deterioration in HrQoL | 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) (Taphoorn et al. 2015). | From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first. | 
| Short-term qOS deterioration in NANO scale | 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 (Nayak et al. 2017). | From 3 months after start of treatment, every 3 months until maximum of 10 years or date of death from any cause, whichever came first. | 
| Short-term qOS deterioration due to death | Death due to any cause. | From start of randomization until death from any cause | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Short-term qOS | Defined as qOS as described above (deterioration in NeuroCogFX®, KPI, HRQoL, NANO scale or death) but neglecting the subsequent time interval of 3 months (90 days). | From 3 months after start of treatment until maximum of 10 years or date of death from any cause, whichever came first. | 
| Overall survival (OS) | Defined as the time from randomization until death due to any cause. | From start of randomization until death from 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. | From randomization until the day of first documentation of clinical or radiographic tumor progression or death of any cause, whichever occurs first | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Radiotherapy, Chemotherapy, Temozolomide