A phase I study of the CDK4/6 inhibitor ribociclib (LEE011) in pediatric patients with malignant rhabdoid tumors, neuroblastoma, and other solid tumors Journal Article


Authors: Geoerger, B.; Bourdeaut, F.; DuBois, S. G.; Fischer, M.; Geller, J. I.; Gottardo, N. G.; Marabelle, A.; Pearson, A. D. J.; Modak, S.; Cash, T.; Robinson, G. W.; Motta, M.; Matano, A.; Bhansali, S. G.; Dobson, J. R.; Parasuraman, S.; Chi, S. N.
Article Title: A phase I study of the CDK4/6 inhibitor ribociclib (LEE011) in pediatric patients with malignant rhabdoid tumors, neuroblastoma, and other solid tumors
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 doselimiting 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. ©2017 AACR.
Journal Title: Clinical Cancer Research
Volume: 23
Issue: 10
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2017-05-15
Start Page: 2433
End Page: 2441
Language: English
DOI: 10.1158/1078-0432.ccr-16-2898
PROVIDER: scopus
PUBMED: 28432176
DOI/URL:
Notes: Article -- Export Date: 3 July 2017 -- Source: Scopus
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  1. Shakeel Modak
    250 Modak