Meeting
2016 ASCO Annual Meeting
Phase II study of alisertib, irinotecan, and temozolomide in children with relapsed and refractory neuroblastoma: A report from the New Approaches to Neuroblastoma Therapy (NANT) consortium.
Authors
Steven G. DuBois
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
Steven G. DuBois , Araz Marachelian , Elizabeth Fox , Rachel A. Kudgus , Joel M. Reid , Susan G. Groshen , Jemily Malvar , Rochelle Bagatell , Lars M. Wagner , John M. Maris , Randall Hawkins , Jesse Courtier , Hollie Lai , Fariba Goodarzian , Hiroyuki Shimada , Najee Boucher , Scarlett Czarnecki , Denice D Tsao-Wei , Katherine K. Matthay , Yael P. Mosse
Organizations
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, Children's Hosp Los Angeles, Los Angeles, CA, University of Philadelphia, Philadelphia, PA, Mayo Clinic, Rochester, MN, Department of Oncology, Mayo Clinic, Rochester, MN, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA, Children's Hospital of Philadelphia, Merion Station, PA, Markey Cancer Center, University of Kentucky, Lexington, KY, Children's Hospital of Philadelphia, Philadelphia, PA, University of California, San Francisco, San Francisco, CA, Children's Hospital Los Angeles, Los Angeles, CA, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, Children's Hospital of Los Angeles, Los Angeles, CA, UC San Francisco, San Francisco, CA, The Children's Hospital of Philadelphia, Philadelphia, PA
Research Funding
Pharmaceutical/Biotech Company
Background: In phase I testing in 22 patients with neuroblastoma, the maximum tolerated dose of alisertib tablets with irinotecan/temozolomide was 60 mg/m2/dose. This combination showed significant activity [31.8% response rate; 52.4% 2-year PFS]. This study sought to: confirm the activity of this regimen; evaluate an alisertib oral solution (OS); and identify predictors of response and toxicity. Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose x 7 days), irinotecan (50 mg/m2/dose IV x 5 days), and temozolomide (100 mg/m2/dose orally x 5 days) in patients 1-30 years of age with relapsed/refractory neuroblastoma. The primary endpoint was best response. Secondary endpoints were toxicity, PFS, and pharmacokinetics. A cohort was treated with alisertib OS at 45 mg/m2, a dose anticipated to be bioequivalent to 60 mg/m2 tablets. Exploratory analyses evaluated predictors of response and toxicity using data from phase I, II, and OS cohorts. Results: Twenty and 12 patients were treated in phase II and OS cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, 4 responses (20%) were observed as well as 4 patients with minor responses. The 1-year PFS was 64.5%. In the OS cohort, 3 patients (25%) had first course dose-limiting toxicity (DLT). Two of 12 patients had objective responses (16.6%) and 1 had a minor response. The alisertib OS at 45 mg/m2 had higher median Cmax (8.7 vs. 3.9 mM) and exposure (58 vs. 45 mM·hr) compared to tablets at 60 mg/m2. Across 54 patients in all cohorts, there were trends to suggest that MYCN amplification and prior irinotecan treatment were associated with lower response rates. Alisertib exposure and trough concentrations were associated with higher rates of first course DLT. Conclusions: Alisertib with irinotecan/temozolomide is an active combination. Alisertib oral solution at 45 mg/m2 is tolerable in this context. Additional studies of biomarkers of response and toxicity are ongoing. Clinical trial information: NCT01601535
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Abstract Details
Session Type
Poster Session
Session Title
Pediatric Oncology
Track
Pediatric Oncology
Sub Track
Pediatric Solid Tumors
Clinical Trial Registration Number
NCT01601535
Citation
J Clin Oncol 34, 2016 (suppl; abstr 10556)
DOI
10.1200/JCO.2016.34.15_suppl.10556
Abstract #
10556
Poster Bd #
247
Abstract Disclosures
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