Combination Therapy for the Treatment of Diffuse Midline Gliomas

Conditions

• Diffuse Intrinsic Pontine Glioma
• Diffuse Midline Glioma, H3 K27M-Mutant
• Recurrent Diffuse Intrinsic Pontine Glioma
• Recurrent Diffuse Midline Glioma, H3 K27M-Mutant
• Recurrent WHO Grade III Glioma
• WHO Grade III Glioma

Eligibility Criteria

Sex

ALL

Age

2 Years - 39 Years

Healthy Volunteers

Not accepted

Interventions

• ONC201 — DRUG
  Given orally (PO)
• Radiation Therapy — RADIATION
  Undergo radiation therapy
• Paxalisib — DRUG
  Given PO
• DNX-2401 — DRUG
  DNX-2401 is an oncolytic adenovirus that will be administered through direct intratumoral infusion of DNX-2401 via a specialized Neuro Ventricular Cannula.

Study Details

This phase II trial determines if the combination of ONC201 with different drugs is effective for treating participants with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for participants with DMGs, and there are few treatment options. This trial will utilize an adaptive platform design in that the different treatment arms for each cohort will be opened and closed based on ongoing preclinical investigation as well as evolving outcome data from the trial. Novel agents will be continuously added to this study as pre-clinical data emerge to suggest additive or synergistic activity when combined ONC201. Should a novel agent not have an RP2D at the time of incorporation into this study, a phase 1 lead-in will be performed prior to initiation of combination therapy (via study amendment).

Key Dates

Start date

Oct 20, 2021

Status verified

Dec 2025

Primary completion

Dec 31, 2027

Completion

Jun 30, 2029

Study Design

Enrollment

360 participants (estimated)

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Arms

• Experimental: NOT CURRENTLY ENROLLING - ARM 2: ONC201 (Day -1), Radiation+ONC201, Paxalisib+ONC201
  Participants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO daily (QD). Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
• Experimental: NOT CURRENTLY ENROLLING - ARM 4: ONC201 (Day -1,-2), Radiation+ONC201, Paxalisib+ONC201
  Participants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity
• Experimental: NOT CURRENTLY ENROLLING - ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201
  Participants may receive a safety lead in of ONC201. During trial validation phase, participants without prior biopsy receive paxalisib PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive paxalisib PO daily during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
• Experimental: Cohort 4 - Dose Escalation, Starting Dose 2 (625mg ONC201)
  Participants will receive a safety lead in of 625mg (or weight-adjusted adult equivalent RP2D for pediatrics) of ONC201 on Day 1 and 2 of each week. During the target validation phase, participants without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. For participants receiving non-interventional radiation/re-irradiation per standard of care treatment, participants will receive 625 mg as the starting dose of ONC201 Days 1 and 2 on a weekly basis during radiation. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity
• Experimental: Cohort 5 - ONC201 + Targeted therapies
  Participants will receive a starting dose of 625mg (or weight-adjusted adult equivalent RP2D for pediatrics) of ONC201 on Day 1 and 2 of each week in combination with targeted agents to be selected from approved/available agents based on a rational therapy approach guided by molecular data from the tumor tissue or cerebral spinal fluid (CSF). For participants receiving non-interventional radiation/re-irradiation per standard of care treatment, prior to starting the combination therapy, participants will receive 625 mg as the starting dose of ONC201 Days 1 and 2 on a weekly basis during radiation. Observations and schedule of events will be issued based on the chosen agent determined to best fit the molecular profile (e.g. BRAFV600E, PDGFRA, FGFR1, NF1).
• Experimental: Cohort 6 - DNX-2401 Repeated Intratumoral Administration
  Participants will receive repeated DNX-2401 intratumoral infusions every 30 days, for a maximum of six injections. During Infusion 1 and Infusion 3, participants will have a biopsy for tumor tissue collection.

Primary Outcome Measure

Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only [ Time Frame: 6 months after diagnosis ]

Central Contacts

• Kelly Hitchner
  (415) 502-1600
  [email protected]

Locations (19)

Find similar trials in Birmingham, AL

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