Recommended phase 2 dose for abemaciclib in combination with irinotecan and temozolomide in pediatric and young adult patients with relapsed/refractory solid tumors: Results from JPCS study (Part A)

<h2>Abstract</h2><h3>Background</h3> Abemaciclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor approved for breast cancer. The CDK4/6 pathway is essential for cell cycle progression. Pediatric cancers often harbor aberrations in this pathway, potentially rendering sensitivity to CDK4/6 inhibition. <h3>Procedure</h3> In this multicenter, open-label, phase 1 trial (JPCS; NCT04238819), children and young adults with relapsed/refractory solid tumors were nonrandomly assigned to standard-dose irinotecan and temozolomide with abemaciclib in a 3 + 3 escalation design with 4 planned dose levels (55, 70 [starting dose], 90, and 115 mg/m² twice daily [BID]). An expansion phase followed. The primary objective was recommended phase 2 dose (RP2D) determination for abemaciclib based on safety and pharmacokinetics. A secondary endpoint was antitumor activity. <h3>Results</h3> Twenty patients enrolled (median age: 12 [7−17] years) with central nervous system tumors as the most frequent diagnosis. The abemaciclib RP2D was 55 mg/m² BID. One of 12 dose-limiting toxicity (DLT)-evaluable patients experienced a DLT (thrombocytopenia) at the RP2D. At the RP2D, the most frequent treatment-related adverse events (TRAEs) were diarrhea (92 %), neutropenia (77 %), thrombocytopenia (62 %), and anemia (62 %), and the most common grade 3/4 TRAEs were neutropenia (62 %), thrombocytopenia, leukopenia, and anemia (each 31 %). At the RP2D, patients received a median of 4 (2−35) cycles of abemaciclib, and best overall response included 1 (5 %) complete response and 6 (46 %) stable disease. Abemaciclib plasma concentrations were within the range associated with efficacy in adults. <h3>Conclusions</h3> Abemaciclib 55 mg/m² BID with irinotecan and temozolomide was tolerable and showed potential antitumor activity in children and young adults with relapsed/refractory malignant solid tumors.