1. Adjuvant Sirolimus Does Not Improve Outcome in Pet Dogs Receiving Standard-of-Care Therapy for Appendicular Osteosarcoma: A Prospective, Randomized Trial of 324 Dogs
- Author
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LeBlanc, Amy K, Mazcko, Christina N, Cherukuri, Aswini, Berger, Erika P, Kisseberth, William C, Brown, Megan E, Lana, Susan E, Weishaar, Kristen, Flesner, Brian K, Bryan, Jeffrey N, Vail, David M, Burton, Jenna H, Willcox, Jennifer L, Mutsaers, Anthony J, Woods, J Paul, Northrup, Nicole C, Saba, Corey, Curran, Kaitlin M, Leeper, Haley, Wilson-Robles, Heather, Wustefeld-Janssens, Brandan G, Lindley, Stephanie, Smith, Annette N, Dervisis, Nikolaos, Klahn, Shawna, Higginbotham, Mary Lynn, Wouda, Raelene M, Krick, Erika, Mahoney, Jennifer A, London, Cheryl A, Barber, Lisa G, Balkman, Cheryl E, McCleary-Wheeler, Angela L, Suter, Steven E, Martin, Olya, Borgatti, Antonella, Burgess, Kristine, Childress, Michael O, Fidel, Janean L, Allstadt, Sara D, Gustafson, Daniel L, Selmic, Laura E, Khanna, Chand, and Fan, Timothy M
- Subjects
Clinical Research ,Pediatric ,Clinical Trials and Supportive Activities ,Rare Diseases ,Orphan Drug ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Cancer ,Amputation ,Animals ,Bone Neoplasms ,Carboplatin ,Chemotherapy ,Adjuvant ,Combined Modality Therapy ,Dog Diseases ,Dogs ,Osteosarcoma ,Pets ,Prospective Studies ,Signal Transduction ,Sirolimus ,Survival Rate ,TOR Serine-Threonine Kinases ,Treatment Outcome ,Amputation ,Surgical ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeThe 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 methodsA 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.ResultsThere 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.ConclusionsIn 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.
- Published
- 2021