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

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Brief Title

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

Official Title

Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication

Brief Summary

      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 phase-3 controlled 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 disease progression, 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.
    


Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Progression-free survival

Secondary Outcome

 Overall survival (for all the comparisons to historical controls)

Condition

Diffuse Intrinsic Pontine Glioma

Intervention

Everolimus

Study Arms / Comparison Groups

 everolimus
Description:  Tablets of 2.5 mg or 10mg. The prescribed dose is 5 mg/m²/day, orally, once daily. Dose will be capped at 10mg once daily. Treatment will be continued until unacceptable toxicity, tumor progression, and/or withdrawal of patient, parents or legal representative consent.
At the time of centrally confirmed relapse or 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) after confirmed disease progression (real-time central review blinded to the treatment allocation), the treatment will also be continued until unacceptable toxicity, tumor progression, and/or withdrawal of patient, parents or legal representative consent.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

368

Start Date

September 2022

Completion Date

September 2031

Primary Completion Date

September 2028

Eligibility Criteria

        Eligibility criteria for the inclusion (registration) in BIOMEDE 2.0 study:

          -  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, H3K28M mutant (ND-DMG) 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.

          -  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:

          -  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 at any dosage during
             the protocol. Bevacizumab is not allowed before surgery. Their used will be taken into
             account when judging the possibility of progression/pseudoprogression.

          -  Any other cancer 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 liberty by a judicial or administrative
             decision or incapable of giving its 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.

          -  Confirmed histological diagnosis of diffuse intrinsic pontine glioma (as per the WHO
             criteria) or 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.

          -  Patients with a suspected DIPG but no histological confirmation (biopsy not
             informative) are eligible for the randomized trial if and only if the radiology is
             typical of a DIPG (mandatory central radiological review) as well as the short
             clinical history (less than three months of pre-existing symptoms). Confirmation of
             the diagnosis of non-DIPG diffuse midline gliomas by central review is needed before
             the randomization of cases of ND-DMG.

          -  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 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.

          -  Ability to swallow capsules. Patients unable to swallow capsules will be treated in
             the everolimus arm without randomization (except if contra-indication to everolimus
             and in this case, patients will not be included in the treatment part of the trial).

          -  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).

          -  ONC201 administration should be avoided for patients with:

               -  Prolongation of QT/QTcF interval (QTc interval > 480 milliseconds) 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.

          -  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 unable to swallow the capsules will be treated with everolimus without
             randomization (except in case of a contra-indication to everolimus).

          -  Patients with a BSA (calculated by Mosteller Formula) below 0.56 cannot receive
             ONC201, they will be treated in the everolimus arm without randomization (except if
             contra-indication to everolimus).

          -  Patients diagnosed without mTOR pathway activation will not be randomized and will be
             treated with the ONC201 arm (except if contra-indication to ONC201). mTOR pathway
             activation will be analysed by IHC showing PTEN loss of expression in the tumor cells.
             In case of doubt, pS6 and/or pAKT expression will be used to confirm mTOR pathway
             activation.

          -  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 with the
             ONC201 arm.

          -  Patients with known hypersensitivity to any component of Everolimus (active substance,
             other rapamycin be treated with the ONC201 arm.

          -  Patients with known hypersensitivity to any component of ONC201 (drug product or
             excipients) will not be randomized and will be treated with the Everolimus arm.
      

Gender

All

Ages

6 Months - N/A

Accepts Healthy Volunteers

No

Contacts

Jacques GRILL, MD, PhD, +33 (0)1 42 11 62 09, [email protected]

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT05476939

Organization ID

2014/2126

Secondary IDs

2014-001929-32

Responsible Party

Sponsor

Study Sponsor

Gustave Roussy, Cancer Campus, Grand Paris

Collaborators

 Chimerix

Study Sponsor

Jacques GRILL, MD, PhD, Study Chair, Gustave Roussy, Cancer Campus, Grand Paris


Verification Date

July 2022