Abstract C002: Phase 1 study of abemaciclib in children with recurrent and refractory solid tumors including malignant brain tumors

Abstract

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) control the transition between G1 and S phases of the cell cycle and are dysregulated in a number of pediatric brain and solid tumors. Abemaciclib, a selective and potent small molecule CDK4/6 inhibitor that crosses the blood brain barrier, limits cell proliferation by suppressing phosphorylation of RB, leading to G1 arrest. Methods: We conducted a phase 1 trial of abemaciclib to determine the maximum tolerated dose (MTD), describe toxicities, and pharmacokinetic (PK) parameters of abemaciclib in pediatric patients with recurrent or refractory solid and CNS tumors. A stratum for newly diagnosed patients with diffuse midline glioma continues to enroll. A CDK mutation was not required, and patients with known RB1 mutations were excluded. Abemaciclib was administered orally twice daily on days 1-28 of a 28-day cycle. Four dose levels were planned (100, 130, 170, and 220 mg/m2/dose) and evaluated using a rolling-six design. Patients were enrolled to a dose expansion cohort at the MTD to ensure adequate PK sampling and safety. PK and pharmacodynamic (PD) analyses are ongoing. Results: The median age of 34 eligible patients was 13.8 years (range: 2.9 - 23.2). Seven (21%) patients had a solid tumor [osteosarcoma (N=2), neuroblastoma (N=1), rhabdomyosarcoma (N=1), desmoplastic small round cell tumor (N=1), clear cell sarcoma (N=1), and MRT of kidney (N=1)] and 27 (79%) patients had a malignant brain tumor [high-grade glioma (N=12), DIPG (N=5), ATRT (N=3), medulloblastoma (N=3), ependymoma (N=2), PNET (N=1), and CNS neuroblastoma (N=1)]. Twenty-three patients were evaluable for DLT. There were 2 cycle 1 DLTs, grade 4 thrombocytopenia and grade 3 vomiting and diarrhea, both occurring at dose level 3. The most common treatment-related cycle 1 adverse events were leukopenia (69%), neutropenia (53%), thrombocytopenia (44%), hypoalbuminemia (41%), anemia (38%), hypophosphatemia (34%) and diarrhea (34%). Conclusions: The pediatric MTD of abemaciclib was 130 mg/m2/dose administered orally twice daily on a 28-day cycle. Abemaciclib was well-tolerated with mainly hematologic toxicity. PK and PD will be used to further inform if 130 mg/m2/dose is the pediatric recommended phase 2 dose. Citation Format: Thomas Cash, Dolly Aguilera, Margaret E Macy, Lindsey Hoffman, Kathleen Dorris, Courtney McCracken, Bradley Hanberry, Robert Castellino, Tobey MacDonald, Cynthia Wetmore. Phase 1 study of abemaciclib in children with recurrent and refractory solid tumors including malignant brain tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C002. doi:10.1158/1535-7163.TARG-19-C002