A combination therapy study using an adaptive platform design for children and young adults with diffuse midline gliomas (DMGs) including diffuse intrinsic pontine gliomas (DIPGs) at initial diagnosis, after radiation therapy, and at the time of progression

Australia, Israel, Netherlands, New Zealand, Switzerland, United States (ICTRP)

ICTRP Studien-ID
NCT05009992 (ICTRP)

Offizieller Titel (Genehmigt von der Ethikkommission)
A Combination Therapy Trial using an Adaptive Platform Design for Children and Young Adults with Diffuse Midline Gliomas (DMGs) including Diffuse Intrinsic Pontine Gliomas (DIPGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression (BASEC)

Wissenschaftlicher Titel
A Combination Therapy Trial Using an Adaptive Platform Design for Children and Young Adults With Diffuse Midline Gliomas (DMGs) Including Diffuse Intrinsic Pontine Gliomas (DIPGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression (ICTRP)

Öffentlicher Titel
Combination Therapy for the Treatment of Diffuse Midline Gliomas (ICTRP)

Untersuchte Krankheit(en)

Diffuse Intrinsic Pontine GliomaDiffuse Midline Glioma, H3 K27M-MutantRecurrent Diffuse Intrinsic Pontine GliomaRecurrent Diffuse Midline Glioma, H3 K27M-MutantRecurrent WHO Grade III GliomaWHO Grade III Glioma

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Untersuchte Intervention

Drug: ONC201Radiation: Radiation TherapyDrug: PaxalisibDrug: DNX-2401

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Studientyp
Interventional (ICTRP)

Studiendesign

Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).

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Ein-/Ausschlusskriterien

• -COHORTS 1, 2, AND 3 CLOSED---

INCLUSION CRITERIA:

COHORT 1A AND 1B:

• 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 Histone 3 lysine 27 - mutant (H3K27M) World Health Organization (WHO) grade III and IV H3 wildtype gliomas.
• Must be within 6 weeks of diagnosis to begin standard of care radiation therapy on study.

COHORT 2A AND 2B:

• Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete 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 III and IV H3 wildtype gliomas.
• Participants must be within 4-14 weeks of completion of radiation. Radiation should have started within 6 weeks of diagnosis.

COHORT 3A AND 3B:

• Diagnosis of recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete 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 III and IV 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.

COHORT 4A AND 4B:

• Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 4B^1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
• Not currently eligible for any other clinical trials that include administration of ONC201.

Cohort 4A^1 and 4B^1 (participants with newly diagnosed DMG prior to radiation): Must be
able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.

Cohort 4A^2 and 4B^2 (participants with newly diagnosed DMG who have completed
radiation): Participants must be within 4-14 weeks of completion of radiation and not
have received additional therapy beyond completion of radiation therapy. Radiation should
have started within 6 weeks of diagnosis.

Cohort 4A^3 and 4B^3 (participants with DMG at progression): Participants must have
evidence of progression and not have received any treatment for this progression and have
not previously received re-irradiation.

COHORT 5

• Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 5^1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
• Not currently eligible for any other clinical trials that include administration of ONC201.
• Multifocal and leptomeningeal disease will be eligible for Cohort 5.
• Participant's tumor must demonstrate one of the following molecular alterations considered targetable by an approved agent:
• BRAFV600E
• PDGFRA (DNA point mutation or amplification with >=5 copy numbers)
• FGFR1 (DNA point mutation, gene fusions, or amplification with >=5 copy numbers)
• NF1

Cohort 5^1 (participants pre-radiation): Must be able to begin standard of care radiation
therapy on study within 6 weeks of diagnosis.

Cohort 5^2 (participants post-radiation): Participants must be within 4-14 weeks of
completion of radiation and not have received additional therapy beyond completion of
radiation therapy. Radiation should have started within 6 weeks of diagnosis.

Cohort 5^3 (participants with progression): Participants must have evidence of
progression and not have received any treatment for this progression and have not
previously received re-irradiation.

All Cohorts (except Cohort 6):

• Age 2 to 39 years
• Participants must have recovered from all acute side effects of prior therapy and be beyond the window for expected ongoing acute toxicities. Any number of prior therapies are allowed.
• Prior ONC201 exposure is allowed, except in participants who have participated in Chimerix trials investigating ONC201 in the upfront setting. Participants who participated in trials investigating ONC201 in the upfront setting will not be eligible at any time, with the exception if participants received ONC201 as part of PNOC022 or other expanded access programs such as German sources of ONC201.
• Participant body weight must be above the minimum necessary for the participant to receive ONC201 (at least 10 kilograms (kg))
• From the projected start of scheduled study treatment, the following time periods must have elapsed: At least 7 days after last dose of a biologic agent or beyond time during which adverse events are known to occur for a biologic agent, 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies (21 days for bevacizumab when used for tumor-directed therapy, guidance on use for pseudo-progression is below), or, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.

o The use of bevacizumab to control radiation therapy-induced edema is allowed (if
used for tumor-directed therapy, please see required time period above).

• Dosing limitations are as follows:
• * Bevacizumab (or equivalent) for up to a maximum of 5 doses, dosing per institutional standard. There is no required washout period.
• Prior use of temozolomide during radiation at maximum of the standard pediatric dosing (defined as 90 mg/m2 /dose continuously during radiation therapy for 42 days) or dexamethasone is allowed. Any other agent given throughout radiation therapy must be discussed with the study chairs prior to beginning the agent.
• Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 3 days prior to baseline magnetic resonance imaging (MRI) scan.
• The participant must have adequate organ function defined as:
• Peripheral absolute neutrophil count (ANC) >= 750/mm^3 (1.0g/l) AND
• Platelet count >= 75,000/mm^3 (100x10^9/l) (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR
• A serum creatinine within the normal limits for age
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age AND
• Serum glutamate pyruvate transaminase (SGPT)(alanine aminotransferase (ALT)) =< 3 x ULN AND
• Serum albumin >= 2 g/Dl
• No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of > 92% while breathing room air.
• Diarrhea < grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0
• No history of congestive heart failure or family history of long QT syndrome.
• ECG must be obtained to verify the Corrected QT Interval (QTc). If an a...

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Primäre und sekundäre Endpunkte

Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only;Progression-free survival at 6 months (PFS6) - Cohorts 2A, 2B Only;Overall survival at 7 months (OS7) - Cohort 3A & 3B Only;Proportion of participants reporting dose-limiting toxicities (DLTs) (Cohort 4);Number of participants requiring dose modification through first cycle of maintenance (Cohort 5);Maximum tolerated number of intratumor infusions of DNX-2401, with a maximum of 6, in participants with thalamic or pontine DMG who have completed radiotherapy (Cohort 6)

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Registrierungsdatum
nicht verfügbar

Einschluss des ersten Teilnehmers
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Sekundäre Sponsoren
The Chad-Tough Defeat DIPG Foundation;Mithil Prasad Foundation;Storm the Heavens Fund;National Institute of Neurological Disorders and Stroke (NINDS);Jazz Pharmaceuticals;Neeve Kolte and Brave Ronil Foundation;Will Meeker Foundation;CV Biomanufacturing;Tough2gether Foundation (ICTRP)

Weitere Kontakte
Sabine Mueller, MD, PhD;Kelly Hitchner, PNOC022@ucsf.edu, (415) 502-1600, University of California, San Francisco, (ICTRP)

Sekundäre IDs
NCI-2021-08386, 1R01NS124607-01, 200821 (ICTRP)

Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
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Weitere Informationen zur Studie
https://clinicaltrials.gov/study/NCT05009992 (ICTRP)