Phase II study of antidisialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma (AOST1421): A report from the Children’s Oncology Group

10508 Background: Treatment of patients with recurrent osteosarcoma (OS) is challenging and novel effective therapies are urgently needed. This study evaluated disease control rate (DCR) in patients with recurrent pulmonary OS, when treated with dinutuximab plus cytokine therapy as compared to a historical benchmark. The rationale for dinutuximab was the ubiquitous ( > 95%) GD2 positivity in OS tumors and cell lines. Methods: AOST1421 was a single-arm phase 2 study. Patients with recurrent pulmonary OS in complete surgical remission were eligible. Patients received five cycles of dinutuximab 70mg/m2/cycle with GM-CSF. Two different dinutuximab infusion schedules were used - 35mg/m2/day over 20 hours (2-day) and 17.5mg/m2/day over 10 hours (4-day) schedule. Primary end point was DCR, defined as proportion of patients event-free at 12 months from enrollment. Events were progressive disease or death within 12 months attributed to treatment or progression. The historical benchmark was AOST0221 with a 12-month DCR of 20% (95% CI 10-34%). Success was defined as ≥16/ 39 patients ( > 40%) event-free at 12 months from enrollment. Secondary objectives included toxicity evaluation and dinutuximab pharmacokinetics (PK). Results: Forty-one patients were enrolled from Nov 2015 - Jan 2018. Thirty nine were eligible and evaluable (age 7-26 yr; median 15 yr). Data current to December 31, 2019 was used for analysis. Accrual rate was higher than expected (22.1 vs. 19.2 patients/ yr.) despite a concurrently open competing study. One of 136 administered therapy cycles met criteria for unacceptable toxicity when one patient receiving the 2-day schedule died after cycle 2 due to an unknown cause, attributed as probably related to protocol therapy. The protocol was revised to allow only the 4-day schedule. Other ≥ Grade 3 toxicities occurring in > 10 % participants were expected dinutuximab toxicities such as pain, diarrhea, hypoxia and hypotension. Dinutuximab did not demonstrate sufficient evidence of efficacy as 27/ 39 patients experienced an event for a DCR of 30.7% (95% CI 17- 47%). PK studies are pending and will be reported. Conclusions: Dinutuximab toxicity in adolescent and young adult OS patients was similar to younger patients. While GD2 remains a relevant target in OS, combination of dinutuximab with GM-CSF did not meet the targeted successful DCR in patients with completely resected tumor. Other strategies for targeting GD2 or dinituximab combination therapy may still be warranted. Clinical trial information: NCT02484443.