E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Histologically WHO grade II (diffuse) or III (anaplastic) astrocytoma, IDHmt without 1p/19q co-deletion (local diagnosis) |
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E.1.1.1 | Medical condition in easily understood language |
Low-grade gliomas (LGGs) are a diverse group of primary brain tumors |
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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 | 10065869 |
E.1.2 | Term | Astrocytoma, low grade |
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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002224 |
E.1.2 | Term | Anaplastic astrocytoma |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine whether in patients with oligosymptomatic isocitrate dehydrogenase mutated (IDHmt) diffuse and anaplastic astrocytoma immediate post-surgery radiotherapy (RT) followed by 12 cycles temozolomide (TMZ) improves the next intervention free survival (NIFS) compared to a post-operative active surveillance period followed by a first treatment, (preferably radio and/or chemotherapy). |
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E.2.2 | Secondary objectives of the trial |
- To assess progression free survival in each arm separately (no comparison between arms)
- To assess if RT followed by 12 cycles TMZ improves overall survival, neurological deterioration free survival, time to deterioration of QOL or cognition function, seizure activity, Patient Reported Outcome compared to active surveillance
- To assess the occurrence of adverse events in both arms
- To collect tumor samples obtained at first surgery for identification of molecular profiles including methylation profiles associated with outcome
- To collect magnetic resonance (MR) images for analysis of radiological patterns associated with early progression, both at baseline and at follow-up
In the active surveillance arm only:
- To assess first intervention free survival (FIFS) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologically WHO grade II (diffuse) or III (anaplastic) astrocytoma, IDHmt without 1p/19q co-deletion (local diagnosis)
- Time since diagnostic surgery or first resection ≤ 6 months
- No need for immediate radiotherapy followed by chemotherapy
- Having seizures only, without functional deficits due to the tumor (but the presence of functional deficits due to the resection is allowed)
- Patients for whom by local judgment an active surveillance policy is a realistic management alternative
- Adults ≥ 18 years of age
- WHO PS 0-2
- Adequate hematological, renal, and hepatic function, as follows:
-Absolute neutrophil count ≥ 1.5 x 109/L
- Platelets ≥ 100 × 109/L
-Serum creatinine ≤ 1.5 times upper limit of laboratory normal (ULN)
-Total serum bilirubin ≤ 1.5 × ULN
-AST and ALT ≤ 2.5 × ULN
-Alkaline phosphatase of ≤ 2.5 × ULN
-Presence of at least one paraffin block from the initial diagnosis for pathology review and translational research. If a representative formalin-fixed, paraffin-embedded (FFPE) block is not available, the collection of optimally 36, minimally 24 x 5 μm, unstained slides is required.
- At the time of randomization presence only of a non-enhancing tumor on T1 weighted contrast enhanced MR images; some faint non-nodular enhancement or enhancement that can be ascribed to the surgical resection or peri-operative ischemia is allowed. Preoperative enhancement is allowed provided this area is resected as shown on postoperative imaging
- Ability to take oral medication
- Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test done within 72 hours prior to randomization
- Patients of childbearing / reproductive potential must agree to use adequate birth control measures, as defined by the investigator, during RT and TMZ treatment and for at least 6 months after the last TMZ cycle. A highly effective method of birth control is defined as those which result in low failure rate (i.e., less than 1% per year) when used consistently and correctly
- Women who are breast feeding must agree to discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment
- Male patients should be advised not to father a child and not to donate sperm up to 6 months after receiving the last dose of TMZ, and to seek advice on cryoconservation of sperm prior to treatment start
- Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and return for the required assessments
- Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations. |
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E.4 | Principal exclusion criteria |
- Presence of signs of increased intracranial pressure after surgery
- Requirement of steroids for control of tumor symptoms
- Presence of uncontrolled seizures after surgery, defined as having both:
- persistent seizures interfering with everyday life activities AND
- failed three lines of anti-epileptic drug regimen, including at least one combination regimen
- Presence of contra-indications for radiotherapy
- Hypersensitivity to dacarbazine (DTIC), to the active substance or to any of the excipients used for TMZ capsules
- Prior chemotherapy, or prior radiotherapy to the brain
- Pregnancy or breastfeeding
- Known HIV, chronic hepatitis B, or hepatitis C infection
- Inability to take oral medication (e.g., frequent vomiting, partial bowel obstruction)
- Concurrent severe or uncontrolled medical disease (e.g., active systemic infection, diabetes, hypertension, coronary artery disease, psychiatric disorder) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the ability of the patient to complete the study
- Prior or second invasive malignancy, except non-melanoma skin cancer, completely resected cervical or prostate cancer (with PSA of less than or equal to 0.1 ng/mL). Other cancers for which the subject has completed potentially curative treatment more than 3 years prior to study entry are allowed
- Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial |
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E.5 End points |
E.5.1 | Primary end point(s) |
Next intervention free survival (NIFS) is defined as the number of days measured from date of randomization until initiation of further treatment after radio- and/or chemotherapy with or without surgery (i.e., second treatment after early treatment or second treatment after active surveillance) or death (any cause) whichever occurs first. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From the date of randomization until initiation of second treatment or death whichever occurs first assessment up to 11.5 years. Timepoints of evaluation are: Median NIFS time, 6, 12-, 18-, 24-month NIFS rate estimates and estimates every 6 months thereafter as relevant for long term survival analysis. |
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E.5.2 | Secondary end point(s) |
In the active surveillance arm only, first intervention free survival (FIFS) is defined as the number of days measured from the date of randomization until initiation of preferably RT/TMZ or any other first therapeutic intervention (second surgery, RT, chemotherapy) or death (any cause) whichever occurs first
In both arms, the following will be analyzed:
- Progression free survival
- Overall survival
- Neurological deterioration free survival
- Time to deterioration of QOL
- Time to deterioration of cognition
- Seizure activity
- Patient reported outcome
- Safety profile (adverse events)
- Correlation between molecular markers and outcome |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For PFS, OS, NDFS:
Median PFS/OS/NDFS time, 6-, 12-, 18-, 24-month PFS/OS/NDFS rate estimates and estimates for every 6 months thereafter as applicable.
For PRO (HRQol)
randomization and every six months until first disease progression or start of next/first treatment.
For neurocognitive function:
randomization then yearly until first disease progression or first/next treatment start.
For PRO (seizure activity)
up to 4 weeks before or after the planned assessment.
For safety profile
from randomization and up to start of next treatment.
For Translational Research
at study entry and at each repeated surgical intervention
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
Radiotherapy, Biobanking, QOL, Neurocognitive testing |
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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 | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 63 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Denmark |
France |
Germany |
Italy |
Netherlands |
Norway |
Spain |
Switzerland |
United Kingdom |
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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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End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients randomized to the early treatment arm have stopped early treatment.
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
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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 | 11 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 11 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |