Universität zu Köln

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

Full text not available from this repository.

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:	Creators Email ORCID ORCID Put Code Geoerger, Birgit UNSPECIFIED UNSPECIFIED UNSPECIFIED Bourdeaut, Franck UNSPECIFIED UNSPECIFIED UNSPECIFIED DuBois, Steven G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Geller, James I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gottardo, Nicholas G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Marabelle, Aurelien UNSPECIFIED UNSPECIFIED UNSPECIFIED Pearson, Andrew D. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Modak, Shakeel UNSPECIFIED orcid.org/0000-0002-7280-1726 UNSPECIFIED Cash, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Robinson, Giles W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Motta, Marlyane UNSPECIFIED UNSPECIFIED UNSPECIFIED Matano, Alessandro UNSPECIFIED UNSPECIFIED UNSPECIFIED Bhansali, Suraj G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dobson, Jason R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Parasuraman, Sudha UNSPECIFIED UNSPECIFIED UNSPECIFIED Chi, Susan N. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language CELL-CYCLE ARREST; LANDSCAPE; CYCLIN-D1; FREQUENT; CRITERIA; PATHWAY; TARGET; FUTURE Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23115