| 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 of ONC201 compared to everolimus, in combination with radiotherapy, in patients with newly diagnosed DMG, K28M mutant or EZHIP+ (non-DIPG DMG, ND-DMG; and DIPG), and in the cohort of ND-DMG alone, in terms of progression-free survival (PFS) from randomization (internal comparison). |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of ONC201 compared to everolimus, in combination with radiotherapy in patients with newly diagnosed DIPG in terms of PFS from randomization (internal comparison).
- To compare the overall survival (OS) from the date of radiological diagnosis between patients with newly diagnosed DIPG having started ONC201 in the current trial, and histologically-proven DIPG historical controls treated within the BIOMEDE 1.0 trial or a similar trial (radiation therapy combined with systemic treatment).
- To compare the overall survival from the date of diagnosis between patients with newly diagnosed ND-DMG, H3K28M mutant having started ONC201 in the current trial, and H3K28M mutant ND-DMG historical controls within the HERBY trial or a similar trial (radiation therapy combined with temozolomide +/- other drug). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for the inclusion (registration) in BIOMEDE 2.0 study:
- Diagnosis Criteria:
o Diagnosis of DIPG (clinical and radiological). As biopsy is not standard for these tumors, an informed consent is required for the necessary histological verification. [Biopsy-part of BIOMEDE 2.0 trial]
or
o Histological diagnosis of DIPG (i.e. H3K28M or EZHIP positive Diffuse Midline Glioma located in the pons) in case the biopsy was performed before study entry. The diagnosis will be defined by 1/ diffuse glioma, 2/ H3K28M mutation or loss of H3K28 trimethylation together with EZHIP overexpression. In this situation, patient will sign the consent after the diagnosis to allow central review and biomarkers assessment thereafter.
or
o Non-DIPG diffuse midline gliomas (ND-DMG), H3K28M mutant or with H3K28 trimethylation loss together with EZHIP overexpression, will be eligible for the trial after biopsy or surgery. As biopsy and surgery is considered as standard practice for these locations, informed consent for the biopsy will not be necessary. Patient will sign the consent after the diagnosis to allow central review and biomarkers assessment thereafter.
Or
oNon-DIPG diffuse midline gliomas (ND-DMG) will be eligible for the trial before the biopsy in case the diagnosis is clinically or radiologically suspected. (..), these patients will be eligible for the treatment part of the trial.
- Eligible for a biopsy, or biopsy material available for the biomarker assessment.
- Age > 6 months, with no upper age limit. Children between 6 months and 3 years will be discussed on a case by case basis for inclusion in the study for the feasibility of the stereotactic biopsy.
- Eligible for cerebral or craniospinal radiotherapy.
- Tumor at diagnosis: no prior chemotherapy for the present cancer; no prior cerebral radiation therapy even for another neoplasm. Surgery is allowed when performed for diagnostic or therapeutic purpose.
- Metastatic diseases or spinal tumors allowed; in this case, patients would receive craniospinal or spinal radiotherapy and medical treatment (everolimus or ONC201) will be postponed and only started after the end of radiotherapy.
- Patients must be affiliated to a social security system or beneficiary of the same according to local requirements.
- Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific procedures are conducted according to local, regional or national guidelines.
Inclusion criteria for the randomization in BIOMEDE 2.0 study:
- Patient enrolled in the BIOMEDE 2.0 study.
- Life expectancy > 12 weeks after the start of study treatment.
- Histological diagnosis of DIPG (as per the WHO criteria) confirmed by central pathology review:
or
Typical radiology of a DIPG (mandatory central radiological review) as well as the short clinical history (less than three months of pre-existing symptoms) in case of suspected DIPG but no histological confirmation (biopsy not informative),
or
Histological diagnosis of ND-DMG confirmed by central pathology review with
o mutation in the histone H3.1, H3.2, H3.3 genes
or
o loss of H3K28me3 and EZHIP overexpression by immunohistochemistry.
- Karnofsky performance status scale or Lansky Play Scale > 50%. The PS should not take the neurologic deficit per se into account. NB: Children and adults with a worse performance status due to glioma-related motor paresis can be included.
- 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 is defined in Appendix 5.
- Negative pregnancy test (serum beta-HCG or urinary test) evaluated within one week prior randomization in sexually active females of reproductive potential.
- Absolute neutrophil count > 1.5 x 10^9/l, Platelets > 100 x 10^9/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 x ULN, creatinine clearance must be > 70 ml/min/1.73 m² (as per local practice).
- Normal coagulation tests within the local reference ranges.
- Written informed consent from parents/legal representative, patient, and age-appropriate assent before randomization according to local, regional or national guidelines. |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria for the inclusion (registration) in BIOMEDE 2.0 study:
- Uncontrolled Spontaneous massive intratumor bleeding. Patients with post-operative bleeding will be allowed to enter the study provided the hemorrhage 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 is not allowed, except corticosteroids and Bevacizumab which are allowed during the protocol. Bevacizumab is not allowed before and until 15 days after the surgery. The use of bevacizumab and corticosteroids will be taken into account when judging the possibility of progression/pseudoprogression.
- Any other cancer diagnosed 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 previously treated with irradiation on the brainstem for another neoplasm.
- Participation in another clinical study with an investigational product while on study treatment.
- Patient under guardianship or deprived of his/her liberty by a judicial or administrative decision or incapable of giving his/her consent.
Exclusion criteria for the randomization in BIOMEDE 2.0 study:
- Current organ toxicity > grade 2 according to the NCI-CTCAE version 5.0 (see Appendix 2) especially cardiovascular or renal disease (including but not limited to: congenital long QT syndrome, nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure despite adequate treatment).
- ONC201 administration should be avoided for patients with:
o Prolongation of QT/QTcF interval (QTc interval > 480 milliseconds) preferably using Frederica’s QT correction formula on two ECGs separated by at least 48 hours.
o A history of Torsades de pointes or heart failure, hypokalemia, or family history of prolonged QT Syndrome.
o Required concomitant use of medication(s) known to prolong the QT/QTc interval.
In this case, patients will be treated in the Everolimus arm without randomization (except if contra-indication to Everolimus).
- Pregnant or breastfeeding women.
- Patients with chronic HBV disease compatible with the trial are not excluded from the study. These patients randomized to everolimus treatment will have regular viral load monitoring throughout the study.
- Patients taking strong P450 inhibitors or inducers or PgP inhibitors are not excluded from the study but drug concentration of everolimus should be monitored carefully to avoid toxicity. Preferably alternative medications should be considered. See Appendix 4 for a list of CYP3A4 inducers and inhibitors.
- Patient with known congenital galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption will not be randomized and will be treated in the ONC201 arm (except if contra-indication to ONC201).
- Patients with known hypersensitivity to any component of Everolimus (active substance, other rapamycin derivatives or excipients) will not be randomized and will be treated in the ONC201 arm (except if contra-indication to ONC201).
- Patients with known hypersensitivity to any component of ONC201 (drug product or excipients) will not be randomized and will be treated in the Everolimus arm (except if contra-indication to Everolimus). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From randomization defined as the time between date of randomization and unequivocal clinical or radiological progression confirmed by central review, or death whatever the cause. |
|
| E.5.2 | Secondary end point(s) |
1) Overall survival
2) Progression-free survival after first progression
3) Safety of the diagnostic biopsy-based procedure
4) Safety profile |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) From the date of radiological diagnosis to the date of death from any cause. For the internal comparison of OS between randomized groups, the overall survival will be defined from the date of randomization to the date of death from any cause.
2) From the date of progression to the date of subsequent progression or death from any cause, in order to describe the outcome after progression.
3) Will be evaluated by the complication rate, the severity of the complications (including prolongation of the hospital stay) and their duration (including delay for starting treatment).
4) Will be assessed using the NCI-CTC v5.0 criteria, during radiotherapy and during the entire duration of the administration of the drug. |
|
| 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) | 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 | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 |
| Switzerland |
| Canada |
| United Kingdom |
| Austria |
| Belgium |
| Denmark |
| Finland |
| France |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
|
| 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 | 7 |
| 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 | 9 |
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