Abstract B065: A phase 1 study of abemaciclib, a CDK 4/6 inhibitor, with radiation in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)
Authors: Cash Thomas , Aguilera Dolly , He Zhulin , Schink Melissa , Sykes Amanda , Pitou Celine , Connelly Erin , Eaton Bree , Esiashvili Natia , Mangum Ross , Macy Margaret E. , Castellino Robert C. , Fangusaro Jason , MacDonald Tobey J. , Wetmore Cynthia , Hoffman Lindsey 
Published: September 2024

Abstract
BACKGROUND: Cyclin-dependent kinases 4 and 6 (CDK 4/6) control cell cycle progression through phosphorylation of Rb. Tumor tissue studies in diffuse intrinsic pontine glioma (DIPG) demonstrate frequent alterations in cell cycle regulatory proteins, including CDK 4/6, and infrequent deletions in Rb1. Preclinical DIPG studies have demonstrated prolonged survival when CDK 4/6 inhibition is added to radiation therapy (RT) compared to RT alone. Abemaciclib is a selective and potent, orally bioavailable small molecule CDK 4/6 inhibitor that crosses the blood brain barrier. We conducted a Phase 1 trial to determine the maximum tolerated dose (MTD) of abemaciclib administered concurrently with RT, and to describe the toxicity and pharmacokinetic (PK) profile, in patients with newly diagnosed DIPG. METHODS: Patients 2-25 years of age with newly diagnosed DIPG were eligible. A CDK 4/6 pathway alteration 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 (DLs) were evaluated using a rolling-six design: 75 (DL0), 100 (DL1), 130 (DL2), and 170 (DL3) mg/m2/dose. Abemaciclib started concurrently with RT and was continued as maintenance after completion of RT until the patient experienced progression or unacceptable toxicity. The 6-week duration of RT (54 Gy in 30 fractions) constituted the dose-limiting toxicity (DLT) evaluation period. The PKs of abemaciclib were evaluated at serial timepoints. RESULTS: Median age of the 22 enrolled patients was 7.1 years (range: 2.6 - 20.1). Eleven (50%) patients were biopsied; 10 were histologically defined as H3K27M mutant diffuse midline glioma. In seventeen DLT-evaluable patients, there was 1 DLT during the DLT evaluation period, grade 3 nausea that occurred on DL3. There were 5 DLTs during maintenance: 3 episodes of prolonged grade 3 neutropenia (DL1=1 and DL2=2) and one episode of grade 4 neutropenia (DL0), and grade 3 weight loss (DL3). The predominant abemaciclib-related toxicities were low-grade and hematologic in nature, including leukopenia (80%), lymphopenia (70%), neutropenia (65%), diarrhea (60%), anemia (50%), and nausea (45%). PK analysis demonstrated that abemaciclib exposure increased with increasing dose. The apparent clearance (CL/F) increased with increasing weight/body surface area, and there was extensive variability in exposure across doses and weight ranges. Mean abemaciclib trough concentrations achieved the target associated with preclinical and clinical efficacy (200 ng/mL) at the 130 and 170 mg/m2 dose levels. The median progression-free survival for all patients was 7.5 months (range: 3.0-21.3) and median overall survival was 12.4 months (range: 2.6-29.0); 2 (10%) patients survived &gt; 24 months. CONCLUSIONS: The MTD of abemaciclib administered concurrently with RT to pediatric patients with newly diagnosed DIPG was 170 mg/m2/dose administered orally twice daily on a 28-day cycle. Abemaciclib was well-tolerated with mainly low-grade hematologic toxicity and diarrhea.
Citation Format: Thomas Cash, Dolly Aguilera, Zhulin He, Melissa Schink, Amanda Sykes, Celine Pitou, Erin Connelly, Bree Eaton, Natia Esiashvili, Ross Mangum, Margaret E. Macy, Robert C. Castellino, Jason Fangusaro, Tobey J. MacDonald, Cynthia Wetmore, Lindsey Hoffman. A phase 1 study of abemaciclib, a CDK 4/6 inhibitor, with radiation in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B065.