Efficacy of ONC201 and Everolimus with Radiotherapy in Newly Diagnosed Diffuse Midline Gliomas H3K28M Mutant or EZHIP Positive Patients

Trial ID: 2023-506027-29-00
Protocol: CSET 2014/2126
Sponsor: Institut Gustave Roussy

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Diseases & Conditions

Brain stem glioma

Objectives

The primary objective of the study is to evaluate the **efficacy** of ONC201 compared to everolimus, in combination with radiotherapy, in patients with newly diagnosed diffuse midline gliomas (DMG), K28M mutant or EZHIP positive, including both non-diffuse intrinsic pontine glioma (ND-DMG) and diffuse intrinsic pontine glioma (DIPG), as well as in the cohort of ND-DMG alone. The evaluation focuses on progression-free survival (PFS) from randomization, which is clinically relevant as it may provide insights into the potential benefits of ONC201 in delaying disease progression in these patient populations.

Secondary objectives include: - Evaluating the efficacy of ONC201 compared to everolimus, in combination with radiotherapy, in terms of PFS from randomization in patients with newly diagnosed DIPG. - Comparing overall survival (OS) from the date of radiological diagnosis between patients with newly diagnosed DIPG treated with ONC201 and historical controls from the BIOMEDE 1.0 trial. - Comparing OS from the date of diagnosis between patients with newly diagnosed ND-DMG, H3K28M mutant treated with ONC201 and historical controls from the HERBY trial. - Comparing OS from the date of randomization between randomized groups, considering ND-DMG and DIPG separately, and accounting for treatment received at progression. - Comparing PFS from the date of first progression based on the type of first-line treatment, time to first progression, and treatment received at progression. - Monitoring the safety of the diagnostic procedure (biopsy) in a multicenter setting. - Evaluating the safety profile of the drugs during radiotherapy and throughout the treatment duration. - Assessing the relative benefit/risk ratio between treatment groups using the Q-TWiST approach. - Evaluating the heterogeneity of study treatment efficacy in terms of PFS and OS according to tumor site and known prognostic biomarkers. - Evaluating the possibility for patients to receive targeted therapy at progression based on molecular profiling at diagnosis.

Participants

The clinical trial involves a total of **10 participants** diagnosed with newly identified diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas that are either H3K28M mutant or EZHIP positive. The study population includes **children, adolescents, and adults** with an age range starting from 6 months, with no upper age limit specified. Both **male and female** subjects are included, and the trial acknowledges the inclusion of a vulnerable population. Participants were selected based on specific diagnostic criteria, including clinical and radiological confirmation of DIPG or ND-DMG, with histological verification where applicable. The general health status of participants is considered stable enough to undergo the study procedures, with a life expectancy greater than 12 weeks post-treatment initiation. Lifestyle factors such as diet and physical activity are not specified, but participants must adhere to effective contraception measures if of reproductive potential. The trial does not specify any prior chemotherapy or cerebral radiation therapy for the current cancer, although surgery for diagnostic or therapeutic purposes is permitted. Participants must be eligible for cerebral or craniospinal radiotherapy, and those with metastatic diseases or spinal tumors are allowed, with specific treatment protocols in place. The trial requires participants to be affiliated with a social security system or its equivalent.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **ONC201** compared to **everolimus**, in combination with radiotherapy, for patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMG) that are H3K28M mutant or EZHIP positive. This is a randomized, double-blind, controlled trial with a primary endpoint of progression-free survival from randomization. The trial is expected to run from October 2014 to September 2031, with participants involved for a maximum treatment period of one year.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological diagnosis and performance status. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of progression-free survival and adverse events. The end-of-study visit will conclude the participant's involvement, with final evaluations of overall survival and safety outcomes.

The expected length of participant involvement is contingent upon the progression of the disease and the occurrence of any adverse events. Conditions that may lead to early termination from the study include significant disease progression, unacceptable toxicity, or withdrawal of consent. Participants are required to adhere to effective contraception measures during the study and for six months post-treatment. The trial will adhere to ethical guidelines, ensuring informed consent is obtained from all participants or their legal representatives.

Treatment

The clinical trial involves the administration of several experimental medications, primarily focusing on the evaluation of **everolimus** and ONC201. **Everolimus** is provided in the form of tablets under the brand names Afinitor and Votubia. Afinitor is available in 2.5 mg and 10 mg tablets, while Votubia is available in 2.5 mg and 10 mg tablets. The pharmaceutical form for all these products is a tablet, and the route of administration is oral. The maximum daily dose for **everolimus** is 5 mg/m², with a total maximum dose of 5 mg/m² per day. The treatment period is limited to a maximum of one day. The active substance, **everolimus**, is of chemical origin and is manufactured by Novartis Europharm Limited. The medication is not a paediatric formulation and is not classified as an orphan drug.

ONC201, another experimental medication in the trial, is provided in capsule form. The active substance is chemically synthesized and is identified as 2,4,6,7,8,9-hexahydro-4-((2-methylphenyl)methyl)-7-(phenylmethyl)imidazo(1,2-a)pyrido(3,4-e)pyrimidin-5(1H)-one. The maximum daily dose for ONC201 is 375 mg/m², with a total maximum dose of 375 mg/m² per day. The route of administration is oral, and the treatment period is also limited to a maximum of one day. The manufacturer of ONC201 is Chimerix, Inc. Similar to **everolimus**, ONC201 is not a paediatric formulation and is not classified as an orphan drug.

In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial aims to evaluate the efficacy of ONC201 compared to **everolimus**, in combination with radiotherapy, in patients with newly diagnosed diffuse midline glioma (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. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy

The efficacy of the clinical trial titled "Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication: BIOMEDE 2.0" will be assessed primarily through **progression-free survival (PFS)** from randomization. This is defined as the time between the date of randomization and the occurrence of unequivocal clinical, cytological, or radiological progression confirmed by central review, or death from any cause. In cases of cytological progression in the cerebrospinal fluid (CSF) only, the date of progression will be marked by the date of the CSF analysis. The main analysis will focus on the entire progression-free survival curve, with progression defined according to the RANO and RAPNO criteria.

Secondary endpoints include overall survival, defined from the date of radiological diagnosis to the date of death from any cause, and progression-free survival after the first progression, calculated from the date of progression to the date of subsequent progression or death. The safety of the diagnostic biopsy-based procedure will be evaluated by the complication rate, severity, and duration, including any delay in starting treatment. The safety profile of the drugs will be assessed using the NCI-CTCAE v5.0 criteria, considering all adverse events except those unequivocally related to disease (pseudo)-progression. Additionally, the relative benefit/risk ratio of ONC201 compared to **everolimus** will be assessed using the Q-TWiST approach, which evaluates quality-adjusted time without symptoms of disease or adverse events, based on survival times and adverse events data.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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]
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.
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.
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
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
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
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.

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Exclusion Criteria

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.
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).

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Denmark	Recruiting	01 Oct 2014	15
Finland	Not Yet Recruiting	01 Oct 2014	8
France	Recruiting	01 Oct 2014	371
Greece	Not Yet Recruiting	01 Oct 2014	6
Norway	Not Yet Recruiting	01 Oct 2014	9
Spain	Recruiting	01 Oct 2014	15
Sweden	Recruiting	01 Oct 2014	22