Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma

Abstract

PURPOSE SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort. PATIENTS AND METHODS This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who had received at least one prior line of therapy. Patients were randomly assigned at a ratio of one to one to regorafenib or placebo. Crossover was allowed at time of disease progression. PFS was the primary end point of the study, which was powered to detect a difference of at least 3 months in median PFS. RESULTS Forty-two patients from 12 centers were enrolled between September 2014 and May 2018. Median age was 37 years (range, 18 to 76 years). Patients had received an average of 2.3 prior therapy regimens. Ten patients receiving placebo crossed over to active drug at time of progression. Study enrollment was stopped early, after a data safety monitoring committee review. Median PFS was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0 to 7.6 months) versus 1.7 months (95% CI, 1.2 to 1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.85; P = .017). In the context of the crossover design, there was no statistically significant difference in overall survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation. CONCLUSION The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.

Initial in vivo testing of a multitarget kinase inhibitor, regorafenib, by the Pediatric Preclinical Testing Consortium

“…Regorafenib improved disease stabilization as compared to placebo in a phase 2, randomized, double‐blind, placebo‐controlled study of adult patients with metastatic progressive OS 18 . A second randomized double‐blind phase 2 study found that regorafenib improved time to progression compared to placebo (3.6 months vs 1.7 months, respectively) in adults with progressive, metastatic OS 19 . In a clinical trial of adults with doxorubicin refractory soft tissue sarcoma, regorafenib improved progression‐free survival as compared to placebo for the nonadipocytic sarcoma subtypes studied 20 .…”

Targeted transcriptional profiling of the tumor microenvironment reveals lymphocyte exclusion and vascular dysfunction in metastatic osteosarcoma

“…[69][70][71][72] Recent results from the REGOBONE study (NCT02389244) and the SARC024 study (NCT02048371) report that single-agent regorafenib (pan-VEGFR small molecule inhibitor) prolonged progressionfree survival in patients with recurrent, progressive, and/or metastatic OS who have failed standard of care chemotherapy. 73,74 Both of these studies highlight the therapeutic relevance of VEGFA signaling in advanced OS. Investigating the therapeutic potential of combining antiangiogenic therapy with immune checkpoint blockade is an active area of research.…”

MicroRNA-mRNA networks define translatable molecular outcome phenotypes in osteosarcoma

“…To this end, dasatinib has previously been shown to synergize with doxorubicin in vitro [28]. Finally, a recently published clinical trial of regorafenib vs placebo, (SARC024 [29]), reported increased progression free survival for pre-treated, metastatic osteosarcoma patients. We thus tested if there is an interaction between the miRNA target profile and regorafenib response and we discovered that this indeed is the case, using the previously described cut offs (coefficient >|0.15|, p<0.05).…”