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Clinical Trial
. 2017 May 15;23(10):2433-2441.
doi: 10.1158/1078-0432.CCR-16-2898. Epub 2017 Apr 21.

A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors

Birgit Geoerger  1 , Franck Bourdeaut  2 , Steven G DuBois  3 , Matthias Fischer  4 , James I Geller  5 , Nicholas G Gottardo  6 , Aurélien Marabelle  7 , Andrew D J Pearson  8 , Shakeel Modak  9 , Thomas Cash  10 , Giles W Robinson  11 , Marlyane Motta  12 , Alessandro Matano  13 , Suraj G Bhansali  14 , Jason R Dobson  12 , Sudha Parasuraman  12 , Susan N Chi  15
Affiliations
Clinical Trial

A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors

Birgit Geoerger et al. Clin Cancer Res. .

Abstract

Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors.Experimental Design: Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real-time PK.Results: Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m2 Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m2; n = 1) or grade 4 thrombocytopenia (470 mg/m2; n = 2). Most common treatment-related adverse events (AE) were hematologic: neutropenia (72% all-grade/63% grade 3/4), leukopenia (63%/38%), anemia (44%/3%), thrombocytopenia (44%/28%), and lymphopenia (38%/19%), followed by vomiting (38%/0%), fatigue (25%/3%), nausea (25%/0%), and QTc prolongation (22%/0%). Ribociclib exposure was dose-dependent at 350 and 470 mg/m2 [equivalent to 600 (RP2D)-900 mg in adults], with high interpatient variability. Best overall response was stable disease (SD) in nine patients (seven with neuroblastoma, two with primary CNS MRT); five patients achieved SD for more than 6, 6, 8, 12, and 13 cycles, respectively.Conclusions: Ribociclib demonstrated acceptable safety and PK in pediatric patients. MTD (470 mg/m2) and RP2D (350 mg/m2) were equivalent to those in adults. Observations of prolonged SD support further investigation of ribociclib combined with other agents in neuroblastoma and MRT. Clin Cancer Res; 23(10); 2433-41. ©2017 AACR.

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