| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse Intrinsic Pontine Glioma and Diffuse midline glioma, K27M mutant |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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) |
|
| 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 evaluate the efficacy in terms of overall survival (OS) of erlotinib, everolimus and dasatinib in combination with radiation therapy in patients with a 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 comparisons)
and
*compared to historical control. |
|
| E.2.2 | Secondary objectives of the trial |
with DIPG (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 with
DIPG, and also compared to historical controls;
*To evaluate the whole strategy by estimating the overall and
progression-free survival of the entire cohort of patients with DIPG (by
pooling the different treatment arms) and comparing it to historical
controls. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
*Diagnosis of DIPG (clinical and radiological, or histological in case the
biopsy was performed before study entry)
*Non-brainstem diffuse midline gliomas, H3K27M mutant (NB-DMG), will
be eligible for the trial after biopsy or surgery.
*DIPG or NB-DMG 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 (if diagnosis of DIPG /NB-DMG 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 < 30 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.
*Eligibility criteria for the study (see above)
*Confirmed histological diagnosis of diffuse intrinsic pontine glioma
(grade II, III, IV WHO), or NB-DMG confirmed by central pathology
review .
*Life expectancy > 12 weeks after the start of study treatment
*Karnofsky performance status scale or Lansky Play Scale > 50%.
*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 within the local reference ranges
*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).
*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
*Negative pregnancy test evaluated in the last week in sexually active
females of reproductive potential
*Written informed consent given by the patient / legal representative
for treatment |
|
| E.4 | Principal exclusion criteria |
*Spontaneous massive intratumour bleeding. Patients with postoperative bleeding will be allowed to enter the study provided the hemmorhage is controled. Same rule applies for the other post-operative complications (infection, CSF leakage, absence of wound closure, subdural collection…).
*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
*PTEN-positivity (evaluated by IHC) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| OS is defined as the time between date of randomisation and death whatever the cause. For the comparison to historical controls, the overall survival is computed from the date of biopsy (or initial surgery). The main analysis will be based on the whole survival curve also. |
|
| E.5.2 | Secondary end point(s) |
Effcicacy endpoints
*2-year OS
*Progression-free survival
Safety
The safety 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 adverse events and text fields for unexpected events and other less frequent toxicities. For each experimental treatment given in combination with radiotherapy, adverse events will be carefully monitored, based on the estimated proportion of patients experiencing Grade 3/4 CTCAE adverse event reported as a SAE, both in the first 8 weeks of treatment and on
the whole treatment duration, excluding symptoms that are related to tumour progression or pseudi progression (neurological deterioration, increased intracranial pressure)
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 (including whole exome sequencing and RNAsequencing).
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: monovoxel or 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). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Effcicacy endpoints
*2-year OS
*Progression-free survival from the date of biopsy/initial surgery (or date of randomisation for the comparison of randomised groups) to the date of unequivocal clinical or radiological progression, or death whatever the cause.
Safety
For each experimental treatment given in combination with radiotherapy, toxicity will be carefully monitored, based on the estimated proportion of patients experiencing Grade 3/4 CTCAE adverse event reported as a SAE, both in the first 8 weeks of treatment and on the whole treatment duration. |
|
| 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 | No |
| 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.8.3 |
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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 62 |
| 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 |
| Finland |
| France |
| Ireland |
| Italy |
| Netherlands |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
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