| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018338 |
| E.1.2 | Term | Glioma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10030288 |
| E.1.2 | Term | Oligodendroglioma malignant |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| to show superiority of an initial temozolomide plus lomustine (CETEG) chemotherapy 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 qualified Overall Survival (qOS) |
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| E.2.2 | Secondary objectives of the trial |
| Evaluation and comparison of the two groups regarding secondary endpoints (short-term qOS, PFS, OS, complete and partial response rate) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 Permormance status (KPS) ≥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.1
16. Male patients are willing to use contraception.2
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| E.4 | Principal exclusion criteria |
Main 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.
12. QTc time prolongation > 500 ms.
13. Patients under restricted medication for procarbazine, lomustine, vincristine and temozolomide (see list of restricted medication in Appendix A)
14. Liver disease characterized by:
a. ALT or AST (≥ Grade 2 CTCAE v5.0) confirmed on two consecutive measurements
OR
b. 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
c. 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 dacarbazin (DTIC)
22. Patients with hereditary galactose intolerance, complete lactase deficiency or glucose-galactose malabsorption (Temodal contains Lactose). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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 the time from randomization to 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* or
•related to baseline: 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), or
•related to baseline: 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) or
•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).
•death due to any cause,
Primary Safety Endpoint
Determination of Dose Limiting Toxicity (DLT), defined as all adverse events (AEs) coded using Medical Dictionary for Regulatory Activities (MedDRA) ≥ Grade 3 according to the National Cancer Institute Common Terminology Criteria for AE (CTCAE) v5.0 that are definitely, probably, or possibly related to the administration of the investigational agents
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
whatever occurs first. The first four components are only counted as events starting 12 months
(365 days) after randomization. An event with respect to a sustained qOS (primary endpoint) is
then defined as a functional and/or cognitive deterioration (as described above) on 2
consecutive study visits (beginning 12 months (365 days) after randomization§) with an interval
of 3 months (90 days), tolerating a deviation of at most 28 days - only for biometrical analysis
(±28 days for NANO, KPI or HRQoL, NeuroCog FX (exception: first NeuroCog FX-test in the
follow-up-phase on day 365 (+28 days))). Thus, after a first decline in any of the abovementioned
assessments the next study visit has to be within 62 to 118 days (only for biometrical
analysis). |
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| E.5.2 | Secondary end point(s) |
•short-term qOS defined as qOS as described above, but neglecting the subsequent time interval of 3 months (90 days). Patients still alive without one of the above defined functional and/or cognitive deterioration criteria at a study visit or lost to follow-up will be censored at the last date they were known to be alive without deterioration.
•Overall survival (OS) defined as the time from randomization until death due to any cause. Patients still alive will be censored at the last date they were known to be alive.
•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 (whichever occurs first). Patients without a PFS event will be censored at the last disease assessment showing no progression or at baseline if patient has no post-baseline disease assessments. PFS analysis will be based on the central disease assessment by the Central Neuroradiology in the Head Clinic Heidelberg (Wen et al. 2010, Ellingson et al. 2015).
Response rate defined as complete and partial responses according to Response Assessment in Neuro-Oncology (RANO) criteria, which integrate T1/T2 measurements and changes in steroid use (RANO, Wen et al. 2010, Table 3).
Secondary Safety Endpoints
•Type, severity (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0), seriousness, and relatedness of adverse events.
•Karnofsky Performance Index (KPI)
•Vital signs (BP, HR, temperature, body weight)
•Clinical laboratory parameters (hematology, chemistry, urinalysis), ECG
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| for individual patients is defined as the overall study end. Follow-up of each patient will be continued till the last’s patient’s last visit. Premature end of study occurs on patient’s choice (see section 6.5.4. for details), loss to follow-up or death |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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