Geoerger, Birgit, Bourdeaut, Franck, DuBois, Steven G., Fischer, Matthias, Geller, James I., Gottardo, Nicholas G., Marabelle, Aurelien, Pearson, Andrew D. J., Modak, Shakeel ORCID: 0000-0002-7280-1726, Cash, Thomas, Robinson, Giles W., Motta, Marlyane, Matano, Alessandro, Bhansali, Suraj G., Dobson, Jason R., Parasuraman, Sudha and Chi, Susan N. (2017). A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors. Clin. Cancer Res., 23 (10). S. 2433 - 2442. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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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/m(2). Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m(2); n = 1) or grade 4 thrombocytopenia (470 mg/m(2); 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/m(2) [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/m(2)) 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. (C) 2017 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Geoerger, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bourdeaut, FranckUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
DuBois, Steven G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geller, James I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gottardo, Nicholas G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marabelle, AurelienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pearson, Andrew D. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Modak, ShakeelUNSPECIFIEDorcid.org/0000-0002-7280-1726UNSPECIFIED
Cash, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robinson, Giles W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motta, MarlyaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matano, AlessandroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bhansali, Suraj G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dobson, Jason R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parasuraman, SudhaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chi, Susan N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-231157
DOI: 10.1158/1078-0432.CCR-16-2898
Journal or Publication Title: Clin. Cancer Res.
Volume: 23
Number: 10
Page Range: S. 2433 - 2442
Date: 2017
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3265
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL-CYCLE ARREST; LANDSCAPE; CYCLIN-D1; FREQUENT; CRITERIA; PATHWAY; TARGET; FUTUREMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23115

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