Two complete metabolic responses in relapsed/refractory metastatic Ewing sarcoma and one complete response in relapsed/refractory metastatic neuroblastoma headline the phase 1 portion of Actuate’s pediatric study of elraglusib. Across 40 heavily pretreated patients, clinical responses or disease control were reported in 15, including 10 of 19 in the cyclophosphamide/topotecan combination cohort. No maximum tolerated dose was reached in dose escalation.
The company released the phase 1 readout from Actuate-1902, an open-label, multicenter phase 1/2 trial testing elraglusib as monotherapy and with irinotecan-based or cyclophosphamide/topotecan backbones in patients ages 3–21 with refractory malignancies. Based on the signal, Actuate plans to advance elraglusib in Ewing sarcoma in 2026 and evaluate a development path in neuroblastoma. The program holds FDA Rare Pediatric Disease designations for both indications. The phase 1 portion closed in July 2025 after establishing combination feasibility and preliminary antitumor activity, most prominently with cyclophosphamide/topotecan.
Strategically, the company is narrowing to where the biology and operational path align. A GSK-3β inhibitor layered onto a standard cytotoxic backbone squares with a chemo-sensitization thesis and avoids bespoke combination complexity. Focusing on Ewing sarcoma leverages the clearest early efficacy, a concentrated investigator network, and a regulatory environment that has accepted response-driven endpoints in refractory pediatric settings when randomized trials are impractical. The absence of a reached MTD creates room to optimize dose and schedule, but it also puts pressure on defining a disciplined RP2D and sticking to a single regimen to generate interpretable phase 2 data. The dataset’s heterogeneity—multiple backbones, metabolic and anatomic readouts, and small numbers—will require tightening before any registrational conversation.
For sites and CROs, a protocol anchored to cyclophosphamide/topotecan could be easier to operationalize given familiarity, pharmacy flows, and supportive care pathways. That said, claims of complete metabolic response and bone marrow clearance will demand robust central review, harmonized criteria across RECIST/PERCIST and pediatric disease-specific frameworks, and consistent imaging schedules—adding complexity in a small, geographically dispersed population. Regulators will look for coherence between PET and CT responses, durability beyond early cycles, and safety in growth and development, particularly if maintenance monotherapy extends time on treatment. Sponsors and vendors should note the implications for endpoint selection, central reads, and data quality infrastructure, as well as the potential for external controls if randomization against active chemotherapy is not feasible. The Rare Pediatric Disease designations, and the potential voucher upon approval, may influence financing and partnering, but won’t substitute for a clear efficacy narrative.
The next inflection is the phase 2 design: single-arm against historical cyclophosphamide/topotecan outcomes with objective response as primary, or a pragmatic randomized study that could de-risk regulatory review at the cost of slower enrollment. Expect a tighter inclusion strategy in Ewing sarcoma, explicit durability thresholds at 6–12 months, and prespecified imaging adjudication. Neuroblastoma likely progresses via consortia collaboration given mixed but intriguing signals. Watch for RP2D declaration, a final selection of backbone, and commitments from COG/ITCC sites to determine startup velocity. The core risks remain early-stage variability, reliance on metabolic CRs, and the challenge of converting a heterogeneous phase 1 signal into a reproducible, regulator-ready dataset. Delivery will hinge on design discipline, centralized assessments, and swift, multi-country site activation in 2026.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
