Karen D Wright1, Xiaopan Yao1, Wendy B London1, Pei-Chi Kao1, Lia Gore2, Stephen Hunger2, Russ Geyer3, Kenneth J Cohen4, Jeffrey C Allen5, Howard M Katzenstein6, Amy Smith7, Jessica Boklan8, Kellie Nazemi9, Tanya Trippett10, Matthias Karajannis10, Cynthia Herzog11, Joseph Destefano10, Jennifer Direnzo10, Jay Pietrantonio1, Lianne Greenspan1, Danielle Cassidy2, Debra Schissel2, John Perentesis12, Mitali Basu12, Tomoyuki Mizuno12, Alexander A Vinks12, Sanjay P Prabhu13, Susan N Chi1, Mark W Kieran1. 1. Dana-Farber/Boston Children's Cancer and Blood Disorders Center, 450 Brookline Avenue, Boston, Massachusetts, 02215, USA. 2. Children's Hospital Colorado, 13123 E 16th Avenue, Aurora, Colorado, 80045, USA. 3. Seattle Children's Hospital, 4800 Sand Point Way NE, Seattle, Washington, 98105, USA. 4. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N Broadway, Baltimore, Maryland, 21231, USA. 5. New York University Medical Center, 550 1st Avenue, New York, New York, 10016, USA. 6. Children's Healthcare of Atlanta, 1365 Clifton Road NE, Atlanta, Georgia, 30322, USA. 7. University of Florida Health Shands Cancer Hospital, 1515 SW Archer Road, Gainesville, Florida, 32608, USA. 8. Phoenix Children's Hospital, 1919 E Thomas Rd, Phoenix, Arizona, 85016, USA. 9. OHSU Doernbecher Children's Hospital, 700 SW Campus Drive, Portland, Oregon, 97239, USA. 10. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York, 10065, USA. 11. MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA. 12. Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio, 45229, USA. 13. Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts, 02115, USA.
Abstract
BACKGROUND: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS: Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.
BACKGROUND: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS: Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.
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