Adjuvant sirolimus does not improve outcome in pet dogs receiving standard-of-care therapy for appendicular osteosarcoma: A prospective, randomized trial of 324 dogs

Amy K. LeBlanc, Christina N. Mazcko, Aswini Cherukuri, Erika P. Berger, William C. Kisseberth, Megan E. Brown, Susan E. Lana, Kristen Weishaar, Brian K. Flesner, Jeffrey N. Bryan, David M. Vail, Jenna H. Burton, Jennifer L. Willcox, Anthony J. Mutsaers, J. Paul Woods, Nicole C. Northrup, Corey Saba, Kaitlin M. Curran, Haley Leeper, Heather Wilson-RoblesBrandan G. Wustefeld-Janssens, Stephanie Lindley, Annette N. Smith, Nikolaos Dervisis, Shawna Klahn, Mary Lynn Higginbotham, Raelene M. Wouda, Erika Krick, Jennifer A. Mahoney, Cheryl A. London, Lisa G. Barber, Cheryl E. Balkman, Angela L. McCleary-Wheeler, Steven E. Suter, Olya Martin, Antonella Borgatti, Kristine Burgess, Michael O. Childress, Janean L. Fidel, Sara D. Allstadt, Daniel L. Gustafson, Laura E. Selmic, Chand Khanna, Timothy M. Fan

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE: The mTOR pathway has been identified as a key nutrient signaling hub that participates in metastatic progression of high-grade osteosarcoma. Inhibition of mTOR signaling is biologically achievable with sirolimus, and might slow the outgrowth of distant metastases. In this study, pet dogs with appendicular osteosarcoma were leveraged as high-value biologic models for pediatric osteosarcoma, to assess mTOR inhibition as a therapeutic strategy for attenuating metastatic disease progression.

PATIENTS AND METHODS: A total of 324 pet dogs diagnosed with treatment-naïve appendicular osteosarcoma were randomized into a two-arm, multicenter, parallel superiority trial whereby dogs received amputation of the affected limb, followed by adjuvant carboplatin chemotherapy ± oral sirolimus therapy. The primary outcome measure was disease-free interval (DFI), as assessed by serial physical and radiologic detection of emergent macroscopic metastases; secondary outcomes included overall 1- and 2-year survival rates, and sirolimus pharmacokinetic variables and their correlative relationship to adverse events and clinical outcomes.

RESULTS: There was no significant difference in the median DFI or overall survival between the two arms of this trial; the median DFI and survival for standard-of-care (SOC; defined as amputation and carboplatin therapy) dogs was 180 days [95% confidence interval (CI), 144-237] and 282 days (95% CI, 224-383) and for SOC + sirolimus dogs, it was 204 days (95% CI, 157-217) and 280 days (95% CI, 252-332), respectively.

CONCLUSIONS: In a population of pet dogs nongenomically segmented for predicted mTOR inhibition response, sequentially administered adjuvant sirolimus, although well tolerated when added to a backbone of therapy, did not extend DFI or survival in dogs with appendicular osteosarcoma.

Original languageEnglish (US)
Pages (from-to)3005-3016
Number of pages12
JournalClinical Cancer Research
Volume27
Issue number11
DOIs
StatePublished - Jun 1 2021

Bibliographical note

Funding Information:
We extend our gratitude to the QuadW Foundation and to the Morris Animal Foundation grants #D14CA-507, D16CA-518, and D16CA-519 for funding, in part, the work described herein. This work was supported by the Intramural Program of the NCI, NIH (Z01-BC006161, to A.K. LeBlanc and C.N. Mazcko). This project has been funded in whole or in part with Federal funds from the NCI, NIH, under contract no. HHSN261201800001I (to E.P. Berger). This study was supported, in part, by award number grant UL1TR002733 from the National Center for Advancing Translational Sciences and NCI P30 CA016058 (to W.C. Kisseberth and M.E. Brown). Pharmacokinetics analysis was conducted by the Drug Development and Discovery Shared Resource of the University of Colorado Cancer Center with technical assistance from Nathaniel L. Gustafson, and was supported, in part, by NCI P30 CA046934 (to D.L. Gustafson). We thank the University of California, Davis Veterinary Center for Clinical Trials. We thank The Virginia-Maryland College of Veterinary Medicine Clinical Trials Office coordinator, Mindy Quigley. Ohio State University College of Veterinary Medicine Integrated Oncology Service also includes Drs. Emma E. Warry, Joelle M. Fenger, and Vincent A. Wavreille. We thank the Ohio State University Blue Buffalo Veterinary Clinical Trials Office, including Holly Borghese and Dana Nielsen.

Publisher Copyright:
© 2021 American Association for Cancer Research.

PubMed: MeSH publication types

  • Journal Article

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