Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication 2.0 (BIOMEDE 2)
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| ClinicalTrials.gov Identifier: NCT05476939 |
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Recruitment Status :
Recruiting
First Posted : July 27, 2022
Last Update Posted : March 1, 2024
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The BIOMEDE 2.0 study is the second stage of the BIOMEDE multi-arm, multistage rolling programme (adaptive platform protocol).
It is a multicenter, randomized, open-label, controlled phase-3 trial evaluating efficacy of ONC201 in comparison with everolimus (primary objective based on internal comparison) and subsequently to historical controls.
Two treatment groups will be compared. A switch between treatment groups is allowed after confirmation of the disease progression (real-time central review blinded to the treatment arm allocation). Study treatment will be continued until centrally confirmed disease progression (either radiologically or histologically), unacceptable toxicity or consent withdrawal.
The final conclusion of the trial will be successful for ONC201, if ONC201 is found significantly superior to everolimus in terms of centrally-reviewed PFS (Progression-free survival) from randomization (internal comparison) either overall, considering ND-DMG and DIPG-patients together, or in the subgroup of ND-DMG patients alone. In other cases, Everolimus will remain the standard arm unless it appears associated with an excess of toxicity compared to ONC201 which could then be discussed as a new standard.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Diffuse Intrinsic Pontine Glioma Diffuse Midline Glioma, H3 K27M-Mutant | Drug: Everolimus Drug: ONC201 Radiation: Radiotherapy | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 409 participants |
| Allocation: | Randomized |
| Intervention Model: | Crossover Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication |
| Actual Study Start Date : | September 29, 2022 |
| Estimated Primary Completion Date : | September 2028 |
| Estimated Study Completion Date : | September 2031 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: everolimus
Tablets of 2.5 mg or 10 mg. The prescribed dose is 5 mg/m²/day, orally, once daily. Dose will be capped at 10 mg once daily. Study treatment will be continued until centrally confirmed disease progression (either radiologically or histologically), unacceptable toxicity, or consent withdrawal. At the time of centrally confirmed progression, patients will be allowed to switch to the other arm in case no better option is available after considering the results of the molecular profiling. In case of switch (everolimus to ONC201 or vice-versa), the patient will observe a wash-out period before starting:
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Drug: Everolimus
Tablets of 2.5 mg or 10 mg. The prescribed dose is 5 mg/m²/day, orally, once daily. Dose will be capped at 10 mg once daily.
Other Names:
Radiation: Radiotherapy All patients will be treated with 30 conventional single daily fraction of 1.8 Gy to a total of 54 Gy over a planned period of 6 weeks. Dose may be increased up to 60 Gy for adult patients with supratentorial ND-DMG. The clinical target volume will include all the areas of abnormality on T2/FLAIR sequences with a 1-cm margin. Radiotherapy will have to start within a maximum of 4 weeks for DIPG, up to 6 weeks for other DMG H3K28-altered (ND-DMG), after the biopsy or last surgery. The study medication will be started at Day 1 (+3 days max) of radiotherapy. Reirradiation is permitted only at disease progression according to local practice. In case of metastatic disease or intramedullary tumors, patients can be included in the study. In this situation, radiotherapy will have to start within a maximum of 4 weeks for DIPG, up to 6 weeks for other DMG H3K28-altered (ND-DMG), after the biopsy or last surgery while targeted treatment will start at the end of the irradiation. |
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Experimental: ONC201
Capsules of 125 mg. The prescribed dose is 375 mg/m2, once daily at Day 1 and Day 2 of each week. Dose will be capped at 625 mg per dose. Study treatment will be continued until centrally confirmed disease progression (either radiologically or histologically), unacceptable toxicity, or consent withdrawal. At the time of centrally confirmed progression, patients will be allowed to switch to the other arm in case no better option is available after considering the results of the molecular profiling. In case of switch (everolimus to ONC201 or vice-versa), the patient will observe a wash-out period before starting:
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Drug: ONC201
Capsules of 125mg. The prescribed dose is 375mg/m2 per dose, once daily at Day 1 and Day 2 of each week. Dose will be capped at 625 mg per dose. Radiation: Radiotherapy All patients will be treated with 30 conventional single daily fraction of 1.8 Gy to a total of 54 Gy over a planned period of 6 weeks. Dose may be increased up to 60 Gy for adult patients with supratentorial ND-DMG. The clinical target volume will include all the areas of abnormality on T2/FLAIR sequences with a 1-cm margin. Radiotherapy will have to start within a maximum of 4 weeks for DIPG, up to 6 weeks for other DMG H3K28-altered (ND-DMG), after the biopsy or last surgery. The study medication will be started at Day 1 (+3 days max) of radiotherapy. Reirradiation is permitted only at disease progression according to local practice. In case of metastatic disease or intramedullary tumors, patients can be included in the study. In this situation, radiotherapy will have to start within a maximum of 4 weeks for DIPG, up to 6 weeks for other DMG H3K28-altered (ND-DMG), after the biopsy or last surgery while targeted treatment will start at the end of the irradiation. |
- Progression-free survival [ Time Frame: Until 2 years after inclusion of the last patient ]Defined as the time between date of randomization and unequivocal clinical, cytological or radiological progression confirmed by central review, or death whatever the cause.
- Overall survival (for all the comparisons to historical controls) [ Time Frame: Until 5 years after randomization of the last patient ]Defined from the date of radiological diagnosis to the date of death from any cause.
- Overall survival (for the internal comparison between randomized groups) [ Time Frame: Until 5 years after randomization of the last patient ]Defined from the date of randomization to the date of death from any cause.
- Progression-free survival after first progression [ Time Frame: Until 5 years after randomization of the last patient ]It 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.
- Complication rate of the diagnostic biopsy-based procedure [ Time Frame: Until 5 years after randomization of the last patient ]
- Severity of the complications (including prolongation of the hospital stay) of the diagnostic biopsy-based procedure [ Time Frame: Until 5 years after randomization of the last patient ]
- Duration of the complications (including delay for starting treatment) of the diagnostic biopsy-base procedure [ Time Frame: Until 5 years after randomization of the last patient ]
- Safety profile of the drugs [ Time Frame: Until 5 years after randomization of the last patient ]Using the NCI-CTC v5.0 criteria, during radiotherapy and during the entire duration of the administration of the drug, considering all adverse events except adverse events unequivocally related to the disease (pseudo)-progression.
- Relative benefit/risk ratio of ONC201 compared to everolimus [ Time Frame: Until 5 years after randomization of the last patient ]It 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).
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| Ages Eligible for Study: | 6 Months and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Eligibility criteria for the inclusion (registration) in BIOMEDE 2.0 study:
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Diagnosis 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]. OR
- 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
- 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
- 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.
- 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.
Non eligibility 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.
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 mutation in the histone H3.1, H3.2, H3.3 genes, or 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.
- 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.
Non Eligibility criteria for the randomization in BIOMEDE 2.0 study:
- Current organ toxicity > grade 2 according to the NCI-CTCAE version 5.0 especially cardiovascular or renal disease (including but not limited to: congenital long QT syndrome, nephrotic syndrome, glomerulopathy, uncontrolled high blood pressure despite adequate treatment).
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ONC201 administration should be avoided for patients with:
- 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.
- A history of Torsades de pointes or heart failure, hypokalemia, or family history of prolonged QT Syndrome.
- 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.
- 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).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05476939
| Contact: Jacques GRILL, MD, PhD | +33 (0)1 42 11 62 09 | jacques.grill@gustaveroussy.fr | |
| Contact: Anne-Sophie BLANC, PharmD | +33 (0)1 42 11 57 02 | annesophie.blanc@gustaveroussy.fr |
Show 32 study locations
| Study Chair: | Jacques GRILL, MD, PhD | Gustave Roussy, Cancer Campus, Grand Paris |
| Responsible Party: | Gustave Roussy, Cancer Campus, Grand Paris |
| ClinicalTrials.gov Identifier: | NCT05476939 |
| Other Study ID Numbers: |
2014/2126 2014-001929-32 ( EudraCT Number ) |
| First Posted: | July 27, 2022 Key Record Dates |
| Last Update Posted: | March 1, 2024 |
| Last Verified: | February 2024 |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
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Children Adolescents Adults Newly diagnosed |
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Glioma Diffuse Intrinsic Pontine Glioma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Brain Stem Neoplasms Infratentorial Neoplasms Brain Neoplasms Central Nervous System Neoplasms Nervous System Neoplasms |
Neoplasms by Site Brain Diseases Central Nervous System Diseases Nervous System Diseases Everolimus TIC10 compound MTOR Inhibitors Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antineoplastic Agents |