Recommended phase 2 dose (RP2D) for abemaciclib in combination with irinotecan (IRN) and temozolomide (TMZ) in pediatric patients with relapsed/refractory solid tumors (JPCS Part A).
Authors: Lassaletta Álvaro , Moreno Lucas , Ogawa Chitose , Ruggiero Antonio , Hoffman Lindsey M. , Pitou Celine , Zhou Yanhong , Hardebeck Molly C. , Knoderer Holly , Juan-Ribelles Antonio 
Published: June 2023

10039 Background: There remains an unmet need to improve outcomes for pediatric patients (pts) with relapsed/refractory solid tumors. Abemaciclib is an orally administered, selective cyclin-dependent kinase (CDK) 4 & 6 inhibitor approved for breast cancer. Based upon preclinical data and the role of CDK4 & 6 in multiple pediatric solid tumor types, we hypothesized that abemaciclib in combination with IRN and TMZ would demonstrate clinical activity to support further pediatric development. This Phase 1b study aimed to determine the RP2D of abemaciclib in combination with IRN and TMZ in this pt population. Methods: This dose escalation study was part A of study JPCS (NCT04238819), and enrolled pts ≤18 years, weighing ≥10 kg, with a body-surface area ≥0.5 m2, and with relapsed/refractory solid tumors, including CNS tumors, that progressed on standard treatment or experienced disease recurrence. IRN (50 mg/m2) and TMZ (100 mg/m2) were administered on days 1-5 of 21-day cycles and remain the same for all dose levels, while abemaciclib was tested on four dose levels: 55, 70, 90, and 115 mg/m2 twice daily (BID). The starting dose was 70 mg/m2 BID for abemaciclib. The maximum tolerated dose was defined as the highest dose level at which < 33% of pts experienced a dose-limiting toxicity (DLT) during Cycle 1. The primary objective, determination of the abemaciclib RP2D, was defined based on the totality of safety, tolerability, and pharmacokinetic (PK) results, and confirmed in an expansion cohort. Secondary objectives included safety and response assessments. Results: At the data cut-off of 13 June 2022, a total of 20 pts received abemaciclib at 70 mg/m2 (n = 7) or 55 mg/m2 (n = 13). The most frequent diagnoses (≥3 pts) were medulloblastoma (n = 4), malignant glioma (n = 3), and rhabdomyosarcoma (n = 3). At the starting dose of 70 mg/m2, DLTs were experienced by 3 pts (neutropenia [n = 3; 43%]; gamma glutamyltransferase increased [n = 1; 14%]). The dose was de-escalated to 55 mg/m2, at which one pt (8%) experienced a DLT (thrombocytopenia). High grade adverse events (AEs) were mostly hematological. Discontinuations due to AEs occurred in 2 pts (29%) at 70 mg/m2 and 0 pts at 55 mg/m2. Five pts (71%) at 70 mg/m2 and 4 pts (31%) at 55 mg/m2 achieved a best overall response of stable disease; 1 pt (8%) at 55 mg/m2 achieved a complete response (rhabdomyosarcoma). No partial responses were observed. PK concentrations of abemaciclib at 55 mg/m2 achieved average plasma abemaciclib concentrations of ~150 ng/mL and the abemaciclib Ctrough concentrations appeared reasonably constant over time at ~100 ng/mL. PK concentrations of IRN and TMZ were as expected. Conclusions: The RP2D of abemaciclib is 55mg/m2 BID in combination with IRN and TMZ. This combination appears tolerable with plasma concentrations within the range associated with efficacy in adult studies. Clinical trial information: NCT04238819 .