| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse Intrinsic Pontine Glioma |
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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 | 10006143 |
| E.1.2 | Term | Brain stem glioma |
| 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 |
The main objective of this study is to evaluate how effective each of the trial treatments erlotinib, everolimus and dasatinib are when compared to each other and to patients who have had the same disease in the past but had a different treatment. The effectiveness is measured in terms of overall survival.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
-To compare the overall survival of patients after two years, between sub sets of patients and compared to patients who have had the same disease in the past but had a different treatment.
-To assess the safety of each of the three drugs when given at the same time as radiotherapy, and over the whole duration of trial treatment, as well as the feasibility of giving the drugs continuously.
-To assess the effectiveness of erlotinib, everolimus and dasatinib in comparison with radiation therapy, comparatively between randomised subsets of patients and in comparison to patients who have had the same disease in the past but had a different treatment - in terms of how long patients survive without their disease getting worse.
-To assess the whole trial strategy by estimating the overall survival and survival without disease progression of the entire patient group, and comparing these to patients who have had the same disease in the past but had a different treat |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Eligibility criteria for the BIOMEDE study (pre-screening for the randomised subtrials)
- Diagnosis of DIPG (clinical and radiological, or histological in case the biopsy was performed before study entry)
- DIPG at diagnosis: no prior chemotherapy for the present cancer; no prior cerebral radiation therapy
- NB : Metastatic disease allowed. Patient with metastatic disease are eligible for the study (including the randomised trial if diagnosis of DIPG confirmed). In this situation, radiotherapy will have to start within three weeks after the biopsy while targerted treatment will start at the end of the irradiation
- Age > 6 months and < 25 years. For children below the age of 3 years, inclusion in the study and medical decisions should be discussed with the coordinating investigator.
- Eligible for a biopsy, or biopsy performed for diagnostic purpose and material available for the biomarker assessment
- Eligible for cerebral radiotherapy
- Patient covered by an health insurance if national requirement
- Written informed consent given by patient and/or parents/legal representative for biomarkers assessment and registration in the study.
Common eligibility criteria for the BIOMEDE randomised subtrials
- Eligibility criteria for the study (see above)
- Confirmed histological diagnosis of diffuse intrinsic pontine glioma (grade II, III, IV WHO), confirmed by central pathology review (including the assessment of the loss of H3K27me3 by immunohistochemistry or the presence of a mutation in the histone H3 variant genes). Patients without classical clinical and radiological diagnostic criteria who fulfil the histological and biological criteria of DIPG are eligible for the trial. Pilocytic astrocytoma and ganglioliomas are not eligible.
- Life expectancy > 12 weeks after the start of study treatment
- Karnofsky performance status scale or Lansky Play Scale > 50%. The PS should not take the neurologic deficit per se into account. NB: Children and young adults with a worse performance status due to glioma-related motor paresis can be included.
- Absolute neutrophil count > 1.5 x 109/l, Platelets > 100 x 109/l
- Total bilirubin < 1,5 x ULN, AST and ALT< 2,5 x ULN
- Serum creatinine < 1,5 X ULN for age. If serum creatinine > 1,5 ULN, creatinine clearance must be > 70 ml/min/1,73 m² (EDTA radioisotope GFR or 24 hours urines collection)
- Normal coagulation tests: prothrombin rate (prothrombin time = PT), TCA (PTT), fibrinogen
- No current organ toxicity > grade 2 according to the NCI-CTCAE version 4.0 especially cardiovascular, pulmonary or renal disease (including but not limited to: congenital long QT syndrome, nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure despite adequate treatment, interstitial lung disease, pulmonary arterial hypertension).In case of known or possible cardiac disease, a cardiological advice will be required prior to the inclusion in the randomized trial as a preexisting cardiopathy represents a contra-indication to dasatinib.
- Effective and appropriate contraception for patients (male and female) of reproductive potential during their entire participation in the study and during 6 months after the end of treatment. Effective contraception are defined in CTFG Guidelines “Recommendations related to contraception and pregnancy testing in clinical trials”
- Negative pregnancy test (serum beta-HCG) evaluated in the last week in females of reproductive potential
- Written informed consent given by patient and/or parents/legal representative for treatment and randomization
Eligibility criteria for the subtrials
Eligibility criteria for the different subtrials will be mainly based on biomarkers assessment as detailed in the table above. In addition, contra-indication and precautions for use to specific drugs will be considered. |
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| E.4 | Principal exclusion criteria |
Non eligibility criteria for the study
- Massive intratumour bleeding
- Any other concomitant anti-cancer treatment not foreseen by this protocol
- Any other cancer during the last 5 years
- Uncontrolled intercurrent illness or active infection
- Any other co-morbid condition that in the investigator’s opinion would impair study participation
- Unable for medical follow-up (geographic, social or mental reasons)
- Patient not fulfilling one of the previous eligibility criteria.
- Patient previously treated with irradiation on the brainstem for another neoplasm
- Patient with congenital galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
- Patient not covered by a social security agreement accepted in the treating country if national requirement.
- Pregnant or breast feeding women
- NB: A patient with known hypersensitivity for one the drug or its excipients could still participate to the study and receive one of the other drug(s)
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The main objective of this study is to evaluate the efficacy in terms of overall survival (OS) of erlotinib, everolimus and dasatinib in combination with radiation therapy in patients with DIPG, both
- compared to the other experimental treatments by comparisons between randomised subsets of patients selected according to the biological abnormalities found in their tumour (pairwise direct comparisons), and
- compared to historical control. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall survival is the time between study enrolment (or date of randomisation for the comparison of randomised groups) and death whatever the cause. |
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| E.5.2 | Secondary end point(s) |
*To compare the 2-year OS between randomised subsets of patients
(pairwise comparisons) and compared to historical controls;
*To evaluate the safety profile of each of the three drugs when
administered in combination with radiotherapy, and over the whole
duration of treatment, as well as the feasibility of a continuous
administration of these drugs;
*To evaluate the efficacy in terms of progression-free survival (PFS) of
erlotinib, everolimus and dasatinib in combination with radiation
therapy, comparatively between randomised subsets of patients, and
also compared to historical controls;
*To evaluate the whole strategy by estimating the overall and
progression-free survival of the entire cohort (by pooling the different
treatment arms) and comparing it to historical controls. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Progression-free survival from the date of study enrolment (or date of randomisation for the comparison of randomised groups) to the date of unequivocal clinical or radiological progression, or death whatever the cause. Progression will be defined according to the RANO criteria. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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 | 3 |
| 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 | 21 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Denmark |
| France |
| Ireland |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The end of the study is defined as the Last Patient Last Visit (LPLV). LPLV is defined as the date of the last protocol-specified visit/assessment for the last subject in the study. |
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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