TY - JOUR
T1 - A phase I and surgical study of ribociclib and everolimus in children with recurrent or refractory malignant brain tumors
T2 - A pediatric brain tumor consortium study
AU - DeWire, Mariko D.
AU - Fuller, Christine
AU - Campagne, Olivia
AU - Lin, Tong
AU - Pan, Haitao
AU - Poussaint, Tina Young
AU - Baxter, Patricia A.
AU - Hwang, Eugene I.
AU - Bukowinski, Andrew
AU - Dorris, Kathleen
AU - Hoffman, Lindsey
AU - Waanders, Angela J.
AU - Karajannis, Matthias A.
AU - Stewart, Clinton F.
AU - Onar-Thomas, Arzu
AU - Fouladi, Maryam
AU - Dunkel, Ira J.
N1 - Funding Information:
T. Young Poussaint reports grants from NIH PBTC Neuroimaging Center during the conduct of the study. M.A. Karajannis reports grants from NIH/NCI during the conduct of the study, as well as grants from NIH/NINDS and Sohn Conference Foundation and personal fees from AstraZeneca, QED Therapeutics, CereXis, Recursion Pharma, and Bayer AG outside the submitted work. A. Onar-Thomas reports grants and nonfinancial support from Novartis during the conduct of the study, as well as grants from Pfizer, Novocure, Apexigen, and Incyte; nonfinancial support from Senhwa, Securabio, and AstraZeneca; and personal fees from Roche outside the submitted work. I.J. Dunkel reports grants from NIH during the conduct of the study, as well as nonfinancial support from Apexigen; personal fees and nonfinancial support from AstraZeneca and Roche; other from Bayer; and personal fees from Bristol Myers Squibb/Celgene, Fennec, and QED outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
The trial was partially funded by an NCI Cancer Therapy Evaluation Program PBTC U01 grant: 2UM1CA081457 (UM1). Partial funding was also provided by MSKCC Core Grant (P30 CA008748) and by the American Lebanese Syrian Associated Charities, which provides funding and infrastructure support for the PBTC Operations Core personnel. Novartis provided ribociclib, everolimus, and financial support for trial conduct, patient research costs, operations costs, and correlative studies. Novartis reviewed the article, but did not have a direct role in trial design, patient recruitment, data collection, analyses, or article preparation. The authors thank Stacye Richardson for operations management of the study and the generous commitment of the patients and families for participating in this study.
Publisher Copyright:
2021 American Association for Cancer Research.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - Purpose: Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the MTD/recommended phase II dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection. Patients and Methods: Patients were enrolled in the phase I study according to a rolling 6 design and received ribociclib and everolimus daily for 21 and 28 days, respectively. Surgical patients received ribociclib at the pediatric RP2D (350 mg/m2) for 7–10 days preoperatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts. Results: Sixteen patients were enrolled on the phase I study (median age, 10.3 years; range, 3.9–20.4) and 6 patients in the surgical cohort (median age, 11.4 years; range: 7.2–17.1). Thirteen patients were enrolled at dose level 1 without dose-limiting toxicities (DLT). Two of the 3 patients at dose level 2 experienced DLTs (grade 3 hypertension and grade 4 alanine aminotransferase). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leukopenia. The RP2D of ribociclib and everolimus was 120 and 1.2 mg/m2 for 21 and 28 days, respectively. Steady-state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations, and cerebrospinal fluid (CSF) samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range, 2.22–53.4). Conclusions: Ribociclib and everolimus were well-tolerated and demonstrated pharmacokinetic properties similar to those in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.
AB - Purpose: Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the MTD/recommended phase II dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection. Patients and Methods: Patients were enrolled in the phase I study according to a rolling 6 design and received ribociclib and everolimus daily for 21 and 28 days, respectively. Surgical patients received ribociclib at the pediatric RP2D (350 mg/m2) for 7–10 days preoperatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts. Results: Sixteen patients were enrolled on the phase I study (median age, 10.3 years; range, 3.9–20.4) and 6 patients in the surgical cohort (median age, 11.4 years; range: 7.2–17.1). Thirteen patients were enrolled at dose level 1 without dose-limiting toxicities (DLT). Two of the 3 patients at dose level 2 experienced DLTs (grade 3 hypertension and grade 4 alanine aminotransferase). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leukopenia. The RP2D of ribociclib and everolimus was 120 and 1.2 mg/m2 for 21 and 28 days, respectively. Steady-state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations, and cerebrospinal fluid (CSF) samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range, 2.22–53.4). Conclusions: Ribociclib and everolimus were well-tolerated and demonstrated pharmacokinetic properties similar to those in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.
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UR - http://www.scopus.com/inward/citedby.url?scp=85105270097&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-4078
DO - 10.1158/1078-0432.CCR-20-4078
M3 - Article
C2 - 33547201
AN - SCOPUS:85105270097
SN - 1078-0432
VL - 27
SP - 2442
EP - 2451
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -
