E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diffuse Midline Gliomas, H3K27M mutant |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065443 |
E.1.2 | Term | Malignant glioma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006143 |
E.1.2 | Term | Brain stem glioma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10080666 |
E.1.2 | Term | Diffuse intrinsic pontine glioma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Cohorts 1 and 2 Maintenance Arm(s) Combinations: -To assess efficacy of combination therapy with ONC201 and novel agent in participants with DMG based on median progression-free survival at 6 months (PFS6)
Cohort 3 -To assess efficacy of combination therapy with ONC201 and novel agent in participants with recurrent DMG based on overall survival at 7 months (OS7) |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Cohort 1A and 1B (participants with newly diagnosed DMG prior to radiation therapy) -New diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 1B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO Grade 3 and 4 H3 wildtype gliomas. Cohort 2A and 2B (participants with DMG who have completed radiation therapy) -Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have completed standard-of-care radiation therapy. In cohort 2B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO Grade 3 and 4 H3 wildtype gliomas. -Participants must be within 4-14 weeks of completion of radiation. Cohort 3A and 3B (participants with DMG at progression) -Diagnosis of recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have completed standard-of-care radiation therapy. In Cohort 3B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO Grade 3 and 4 H3 wildtype gliomas. -Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation. |
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E.4 | Principal exclusion criteria |
Cohort 1A and 1B (participants with newly diagnosed DMG prior to radiation therapy) -Prior exposure to radiation therapy. -Thalamic H3K27M DMG* Cohort 2A and 2B -For tumors that do not have a pontine or spinal cord epicenter the following specific exclusion criteria apply: --Thalamic H3K27M DMG that has undergone standard radiation without concurrent therapy (other than temozolomide)* Cohort 1A and 2A (participants with newly diagnosed DMG prior to radiation therapy and who have not previously undergone tumor tissue collection prior to study entry) -Deemed not appropriate for tissue resection/biopsy. Cohort 3A and 3B (participants with DMG at progression) -Prior exposure to re-irradiation for tumor progression. -Patients who participated in trials investigating ONC201 in the upfront setting will not be eligible. Prior ONC201 exposure as part of PNOC022 or expanded access programs will be allowed.* All Cohorts -Diagnosis of a histone H3 wildtype Grade 2 diffuse astrocytoma -Investigational Drugs o Participants who are currently receiving another investigational drug. Investigational imaging agents or agents used to enhance tumor visibility on imaging or during tumor biopsy/resection should be discussed with the study chairs. -Anti-cancer Agents o Participants who are currently receiving other anti-cancer agents. -Participants with a known disorder that affects their immune system, such as HIV or Hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy. Note: Participants that are currently using inhaled, intranasal, ocular, topical or other non-oral or non-IV steroids are not necessarily excluded from the study but need to be discussed with the study chair. -Participants with uncontrolled infection or other uncontrolled systemic illness. -Female participants of childbearing potential must not be pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy (as clinically indicated). -Active illicit drug use or diagnosis of alcoholism. -History of allergic reactions attributed to compounds of similar chemical or biologic composition as the agents used in study. -Evidence of disseminated disease, including multi-focal disease, diffuse leptomeningeal disease or evidence of CSF dissemination. -Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug. -Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration. -Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing antiepileptic drugs (EIAEDs; see Appendix I), during the treatment phase of the study and within 2 weeks prior to starting treatment. Concurrent corticosteroids is allowed.
*Exclusion criteria do not apply to patient of ≤18 years old who have thalamic disease; these patients can still be included in the PNOC022 trial at the Prinses Máxima Center. Exclusion criteria do apply to patients over the age of 18 years old who have thalamic disease. These patients can be enrolled in the ACTION trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint for both Cohorts 1 and 2 is progression-free survival at 6 months (PFS6). PFS6 is defined as the percentage of participants alive and free from progression at 6 months (26 weeks) after the initiation of the combination of the ONC201 with a novel agent given in the maintenance phase of therapy. The primary efficacy endpoint in Cohort 3 is overall survival at 7 months (OS7). OS7 is defined as the percentage of participants alive at 7 months (30 weeks) after the initiation of the combination of ONC201 with a novel agent given in the maintenance phase of therapy. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cohorts 1 and 2 Three interim analysis (including the final one) will be conducted in each cohort for each maintenance combination. The first interim analysis is planned after 11 subjects in each treatment arm have been enrolled, treated, and followed-up for 6 months to perform efficacy evaluation (PFS6 from start of maintenance treatment). Subsequent interim analysis will be conducted after 22 participants in each treatment arm have been enrolled. Final analysis will be conducted after all 33 participants in each treatment arm have been enrolled. Cohort 3 Three interim analysis (including the final one) will be conducted for each maintenance combination, with two interim analyses occurring when the sample size reaches 14 and 28. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
All patients will receive ONC201 and paxalisib in maintenance phase. |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
New Zealand |
Switzerland |
Australia |
Israel |
United States |
Netherlands |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |