| 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 | 17.0 |
| 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 the relative efficacy in terms of two-year overall survival (OS) of erlotinib, everolimus and dasatinib in combination with radiation therapy, between randomised subsets of patients selected according to the biological abnormalities found in their tumour (two-by-two direct comparisons). |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives
-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 protracted administration of these drugs;
-To evaluate the efficacy in terms of overall survival (whole OS curves) and 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.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Diagnosis of DIPG (clinical and radiological, or histological)
-DIPG at diagnosis: no prior chemotherapy for the present cancer; no prior cerebral radiation therapy
-NB : Metastatic disease allowed
-Age > 6 months and < 25 years
-Eligible for a biopsy, or biopsy performed for diagnostic purpose and material available for the biomarker assessment
-Eligible for cerebral radiotherapy
-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 or renal disease (nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure despite adequate treatment). In case of known or possible cardiac disease, a cardiological advice will be required prior to the inclusion in the study if the patient may be allocated to the dasatinib cohort, i.e. presence of PDGFRA gain/amplification in the tumour.
-Effective 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
-Negative pregnancy test (serum beta-HCG) evaluated in the last week in females of reproductive potential
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| E.4 | Principal exclusion criteria |
-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
-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) |
| Overall survival defined the time between study enrolment (or date of randomisation for the comparison of randomised groups) and death whatever the cause. The main analysis will be based on the 2-year OS estimate, but the whole survival curve will be estimated. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Effcicacy endpoints
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.
Toxicity
The toxicity assessment will be conducted using the NCI-CTC V4 on the whole duration of treatment in all treatment arms, using a list of selected toxicity items for the most frequent expected toxicities and text fields for unexpected events and other less frequent toxicities.
For each experimental treatment given in combination with radiotherapy, toxicity will be carefully monitored, based on the estimated proportion of patients experiencing one of the following adverse events, both in the first 8 weeks of treatment and on the whole treatment duration:
-Grade 3 / 4 CTCAE non-haematological toxicity, excluding grade 3 nausea, vomiting, fever, and hepatic toxicity that is rapidly reversible (i.e. returns to < 2.5 x ULN within 2 weeks after study drug discontinuation), and excluding symptoms that are related to tumour progression or pseudo-progression (neurological deterioration, increased intracranial pressure);
-Grade 4 CTCAE neutropenia lasting more than 7 days;
-Grade 4 CTCAE thrombocytopenia persisting longer than 7 days or thrombocytopenia requiring transfusions for more than 7 days.
Each of these adverse event must be communicated directly to the trial manager team and the sponsor coordinator.
Feasibility
-duration of treatment and description of the reasons for treatment discontinuation,
-number of treatment temporary stops and dose-reductions and the description of the reasons for these treatment modifications, and
-estimate of mean dose per week over the whole treatment duration.
Translational study
Response to therapy (PFS and OS) will be correlated to the biomarkers identified before the start and during the course of the study.
Correlation of Multimodal Imaging with Response to Therapy
The value of multimodal imaging to predict response to therapy will be evaluated.
-T1-weighted post-gadolinium imaging will be correlated with outcome since the presence of enhancement could be correlated with survival in one recent study (Hipp 2011).
-MRS: multivoxel proton spectroscopy will be used to assess metabolic profile especially citrate as well as Cho:Cr and Cho:NAA ratios, the latter being correlated to prognosis (Hipp 2011, Steffen-Smith 2011 & 2012).
-DCE-MRI: dynamic contrast-enhanced MRI will be used to assess perfusion since increased perfusion could predict survival (Hipp 2011); the sequences will be analysed centrally with the OLEA software.
-ASL: arterial spin-labelling perfusion MRI will be assessed as a possible surrogate for DCE-MRI. Guidelines from the "ASL Network" (http://www.asl-network.org) will be implemented.
-DWI: diffusion-weighted imaging will be used to assess the apparent diffusion coefficient as a surrogate of tumour cellularity (Gauvain 2001).
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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 | 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 | 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 | 50 |
| E.8.5 | The trial involves multiple Member States | No |
| 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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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
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