Venetoclax in Pediatric and Young Adult Patients With Relapsed/Refractory Solid Tumors: Results of a Phase 1 Study

B-cell lymphoma 2 (BCL-2) is overexpressed in certain solid tumors (including neuroblastoma), representing a promising target. Venetoclax is a first-in-class, oral, highly selective BCL-2 inhibitor. We report safety, pharmacokinetics, and efficacy of venetoclax in children and young adults with relapsed/refractory solid tumors.

M13-833 (NCT03236857) was a Phase 1, open-label, global, two-part study. Patients received age-/weight-adjusted venetoclax (400 or 800 mg/day adult equivalent dose [AED]) continuously or intermittently (Days 1-10 of 21-day cycles) as monotherapy or with cyclophosphamide and topotecan (Cy-Topo; Cy 250 mg/m²/day + Topo 0.75 mg/m²/day; intravenously Days 1-5) and myeloid growth factor support. Primary objectives included safety and pharmacokinetic assessments of venetoclax; secondary objectives included efficacy.

Fifty-nine patients in the neuroblastoma (n = 36; median age: 8 years [range: 1-17]) and solid tumor cohorts (n = 23; median age: 16 years [range: 3-24]) were assessed. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 35/36 (97%) and 21/23 (91%) neuroblastoma and solid tumor patients, respectively; febrile neutropenia was the most common serious TEAE (neuroblastoma 69%; solid tumors 57%). TEAEs leading to discontinuation of venetoclax occurred in 17% (neuroblastoma) and 9% (solid tumors) of patients. No events of tumor lysis syndrome were observed. Peak venetoclax concentrations (T_max) occurred 4-6 h post-dose; exposure was comparable across age/weight subgroups. Objective response rates were 31% (neuroblastoma) and 22% (solid tumors).

Recommended Phase 2 dose of venetoclax was 800 mg/day AED (Days 1-10 of 21-day cycles). Venetoclax combined with Cy-Topo chemotherapy had a predictable safety profile and showed modest clinical activity in these cohorts.