Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradicatio

Phase 1

• Conditions: Diffuse Intrinsic Pontine Glioma and Diffuse midline glioma, K27M mutant; MedDRA version: 20.0Level: PTClassification code 10006143Term: Brain stem gliomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2014-001929-32-SE
• Lead Sponsor: Gustave Roussy

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2016-06-22
• Last Update Posted: 8 July 2024

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 368

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-brainstem diffuse midline gliomas (ND-DMG), H3K28M mutant or
EZHIP-positive , 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, with:
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 gliomarelated
motor paresis can be included.
- Effective and appropriate contraception for patients (male and female)
of reproductive

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 contraindication
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).

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified