PDF: ACTION ONC201
(2024)Objective
Dordaviprone (ONC201) once-weekly or twice-weekly vs placebo after standard radiotherapy — to evaluate overall survival and progression-free survival in pediatric and adult patients with newly diagnosed H3 K27M-mutant diffuse glioma.
Study Summary
• Randomization 1:1:1 to placebo, once-weekly ONC201, or twice-weekly ONC201 — 2-6 weeks post-radiotherapy.
• Primary endpoints: overall survival and RANO-HGG PFS by blinded independent central review.
• Eligibility includes H3 K27M-mutant diffuse glioma (all ages ≥10 kg), KPS/Lansky ≥70, completed first-line RT.
• Prior open-label data: 20% ORR, 11.2-mo duration of response, 21.7-mo median OS with frontline use.
• Currently enrolling at multiple international sites; no efficacy data yet — this paper describes the design.
Intervention
ONC201 (dordaviprone) 625 mg per dose (weight-adjusted to 125 mg increments for patients <52.5 kg) vs placebo. Twice-weekly arm receives ONC201 days 1+2 each week; once-weekly arm receives ONC201 day 1 and placebo day 2; placebo arm receives placebo both days. 28-day cycles.
Inclusion Criteria
H3 K27M-mutant diffuse glioma confirmed by IHC or gene sequencing, completed standard radiotherapy (54-60 Gy), randomized 2-6 weeks post-RT, KPS/Lansky ≥70, weight ≥10 kg (any age).
Study Design
Arms: Placebo vs ONC201 once-weekly vs ONC201 twice-weekly (1:1:1)
Patients per Arm: Target ~150 per arm (enrolling)
Outcome
• Secondary: safety (AEs, lab changes), corticosteroid response, QoL, clinical benefit
• Exploratory: biomarker correlates, PK/PD, cognitive outcomes
• Efficacy results not yet available — trial enrolling; data expected 2025-2027
• Supporting data: integrated analysis (n=50) in recurrent disease showed 20% ORR and 21.7-mo OS vs 12-mo historical control
Clinical Question
In pediatric and adult patients with newly diagnosed H3 K27M-mutant diffuse glioma who have completed standard radiotherapy, does dordaviprone (ONC201) once-weekly or twice-weekly improve overall survival and progression-free survival compared with placebo?
Bottom Line
ACTION (NCT05580562) is an international phase 3 double-blind placebo-controlled trial randomizing pediatric and adult patients with newly diagnosed H3 K27M-mutant diffuse glioma 1:1:1 to placebo, once-weekly ONC201, or twice-weekly ONC201 after standard radiotherapy. Primary endpoints are OS and RANO-HGG PFS. Based on an open-label integrated analysis showing 20% ORR and 21.7-month median OS in recurrent disease, ACTION will provide the definitive phase 3 evidence — currently enrolling, no efficacy results yet.
Major Points
- Phase 3 international double-blind placebo-controlled RCT (ONC201-108, NCT05580562; Arrillaga-Romany 2024 design paper)
- Three-arm 1:1:1 randomization: placebo, once-weekly ONC201, twice-weekly ONC201
- Eligibility: H3 K27M-mutant diffuse glioma (any age ≥10 kg), completed radiotherapy 2-6 weeks before randomization
- Stratification: age (<21 vs ≥21) and risk category (enhancing tumor ≥10 cm², multifocal, or brainstem location)
- Dose: 625 mg per administration for patients ≥52.5 kg; weight-scaled to 125 mg increments for smaller children
- 28-day cycles; treatment continues until progression, unacceptable toxicity, or withdrawal
- Primary endpoints: OS (any cause death) and PFS by RANO-HGG criteria by blinded independent central review
- Secondary: safety, corticosteroid response, PFS in contrast-enhancing disease, clinical benefit, QoL
- Excludes primary spinal tumor, DIPG (since they may receive alternative treatments), leptomeningeal disease, CSF dissemination
- Supporting phase 2 integrated analysis (n=50 recurrent): ORR 20% by RANO-HGG, DOR 11.2 mo, mOS 21.7 mo in frontline use
- ACTION is the definitive trial for regulatory approval; current FDA accelerated approval (April 2025) based on recurrent disease data
- Enrollment ongoing at multiple international sites; efficacy readout expected 2025-2027
Study Design
- Study Type
- Phase 3 international randomized double-blind placebo-controlled parallel-group trial (NCT05580562, ONC201-108)
- Randomization
- Yes
- Blinding
- Double-blind (patient, investigator, and sponsor blinded)
- Sample Size
- 450
- Follow-up
- Until death or withdrawal; survival follow-up Q12W
Primary Outcome
Definition: Overall survival and progression-free survival by RANO-HGG criteria by blinded independent central review (coprimary)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Not yet available; historical mOS ~12 months for newly diagnosed H3 K27M DMG | Not yet available; phase 2 integrated analysis showed 21.7 mo median OS in frontline use | - (Not yet available) | Not yet available (enrolling) |
Limitations & Criticisms
- Design paper only — no efficacy data yet, so clinical decisions cannot yet rest on a randomized readout
- Heterogeneous population (pediatric + adult, brainstem + non-brainstem) may dilute detectable effect; risk stratification helps but cannot eliminate this
- Two-drug-arm design vs single placebo creates inflated type-1 error risk; hierarchical testing plan critical
- Primary supporting evidence (integrated phase 2 analysis) was non-randomized and used historical controls; confirmation bias risk
- DIPG excluded despite being a major H3 K27M-mutant entity — separate trials needed for that population
- Enrollment may be slow given rarity of molecularly confirmed H3 K27M tumors, potentially delaying readout