Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication: BIOMEDE 2.0

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Oct 2014 → ongoing

Decision date (initial)

2024-10-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

NOVARTIS · PHRC FRANCE · ITCC (Imagine for Margo) · CHIMERIX

External identifiers

EU CT number

2023-506027-29-00

EudraCT number

2014-001929-32

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy, Diagnosis

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).

Secondary objectives 10

1. 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).
2. 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
3. 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).
4. To compare overall survival from the date of randomization between randomized groups (internal comparison), overall and considering separately ND-DMG and DIPG. This analysis will consider as well treatment received at progression including re-irradiation and crossover as independent variables
5. To compare progression-free survival from the date of first progression according to the type of first line treatment, the time to first progression and according to the type of treatment received at progression (switch to the other arm or any other therapy; re-irradiation or not).
6. To continue to monitor the safety of the diagnostic procedure (biopsy) in this multicenter setting
7. To evaluate safety profile of the evaluated drugs when administered during radiotherapy and over the whole treatment duration.
8. To evaluate the relative benefit/risk ratio between treatment groups using the Q-TWiST approach.
9. To evaluate heterogeneity of study treatment efficacy (ONC201 versus everolimus, within the trial) in terms of PFS and OS according to tumor site (DIPG versus ND-DMG) and known prognostic biomarkers
10. To evaluate the possibility for patients to be treated at the time of progression with a targeted therapy based on the molecular profiling performed at diagnosis

Conditions and MedDRA coding

Children, adolescents and adults with newly diagnosed diffuse intrinsic pontine glioma and other diffuse midline gliomas H3K28M mutant or EZHIP positive

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 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]
2. 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.
3. Eligibility 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 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 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.
4. Histological diagnosis of DIPG (i.e. H3K28M or EZHIP positive Diffuse Midline Glioma located in the pons) in case the Tumor 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
5. Non-DIPG diffuse midline gliomas (ND-DMG) will be eligible for the trial before the biopsy in case the diagnosis is clinically or radiologically suspected. Informed consent for the biopsy and molecular analysis will be necessary. Then, if the central pathology review concludes to a ND-DMG with H3K28M mutant or H3K28 trimethylation loss together with EZHIP overexpression, these patients will be eligible for the treatment part of the trial
6. Eligible for a biopsy, or biopsy material available for the biomarker assessment.
7. 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.
8. Eligible for cerebral or craniospinal radiotherapy.
9. 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.
10. 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
11. Patients must be affiliated to a social security system or beneficiary of the same according to local requirements
12. Molecular diagnosis of DIPG (i.e. H3K28M) in case a liquid biopsy (CSF or blood) was performed before study entry, in a patient who could not undergo a tumor biopsy because it was too dangerous according to the patient’s clinical condition. The diagnosis will be defined by 1/ DIPG, 2/ H3K28M mutation. In this situation, patient will sign the consent after the diagnosis to allow collection of the local molecular report.

Exclusion criteria 10

1. 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…).
2. 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
3. Any other cancer diagnosed during the last 5 years
4. Uncontrolled intercurrent illness or active infection.
5. Any other co-morbid condition that in the investigator’s opinion would impair study participation
6. Unable for medical follow-up (geographic, social or mental reasons).
7. Patient previously treated with irradiation on the brainstem for another neoplasm
8. Participation in another clinical study with an investigational product while on study treatment
9. Patient under guardianship or deprived of his/her liberty by a judicial or administrative decision or incapable of giving his/her consent.
10. Non Eligibility 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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival from randomization defined as the time between date of randomization and unequivocal clinical, cytological or radiological progression confirmed by central review, or death whatever the cause. In case of cytological progression in the CSF only, the date of progression will be the date of the CSF analysis. The main analysis will be based on the entire progression-free survival curve. Progression will be defined according to the RANO and RAPNO criteria (see Appendix 3).

Secondary endpoints 5

1. For all the comparisons to historical controls, overall survival will be defined from the date of radiological diagnosis to the date of death from any cause.
2. Progression-free survival after first progression will also be computed 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. Safety of the diagnostic biopsy-based procedure 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. Safety profile of the drugs will be assessed using the NCI-CTCAE v5.0 criteria, during radiotherapy and during the entire duration of the administration of the drug, considering all adverse events except AE obviously related to the underlying disease, progression or the pseudo-progression
5. The relative benefit/risk ratio of ONC201 compared to everolimus will be assessed using the Q-TWiST approach (Quality-adjusted time without symptoms of disease or adverse event) evaluated from survival times (overall survival and progression-free survival) and adverse events data (date of occurrence of grade 3+ adverse event) as detailed in the statistical considerations.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Bureau projet Promotion- DRC

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Bureau projet Promotion- DRC

Third parties 1

Locations

4 EU/EEA countries · 121 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 62 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications