Results of a Randomized, Double-Blinded, Placebo-Controlled, Phase 2.5 Study of Saracatinib (AZD0530), in Patients with Recurrent Osteosarcoma Localized to the Lung.

Kristin Baird,Noah Federman,Sheri L Spunt,David M Loeb,Scott H Okuno,Leo Mascarenhas,Mohammed Milhem,Scott M Schuetze,John Glod,Seth M Steinberg,Joseph G Pressey,Neyssa Marina,Robin L Jones,Eve T Rodler,James E Butrynski,Brian Turpin,Denise K Reinke ,John M Goldberg ,Joanne Lagmay ,Arthur P Staddon ,Sant P Chawla ,Lee J Helman

doi:10.1155/2020/7935475

Abstract

Purpose Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. Patients and Methods. Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles. Results Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (p=0.47). Median OS was not reached in either arm. Conclusions Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.

Highlights

Saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on overall survival (OS). is mirrors several studies that showed no effect of saracatinib as a single agent in other solid tumor types [29,30,31,32]. e observed toxicity profile in the present study was similar to those observed in other published studies including hypophosphatemia requiring oral supplementation [30, 31]
In 2009, Hingorani et al published results of their study that examined the effects of dasatinib, a dual Src-Abl kinase inhibitor, on in vitro proliferation, adhesion, and invasion of osteosarcoma cell lines and in preventing the development of spontaneous pulmonary metastases in an orthotopic murine osteosarcoma model. e authors found that dasatinib inhibited Src and its downstream targets and inhibited the adhesion and migration of osteosarcoma cells in vitro, there was no impact on the development of pulmonary metastases in the murine model. ey concluded that Src kinase activation might not be the primary pathway involved in the development of pulmonary metastases in osteosarcoma
They further concluded that Src inhibition combined with inhibition of one or more alternative pathways that are implicated in the metastatic behavior of osteosarcoma might be a rational approach for future clinical trials [33]. is is further supported by examples in the literature highlighting the complex pathways associated with Src signaling, summarized in a comprehensive review in 2015 by Liu et al [34]

Summary

Introduction

E proto-oncogene c-SRC (SRC), a member of the SRC family of protein tyrosine kinases, is a nonreceptor tyrosine kinase that mediates signal transduction affecting various cellular functions, including proliferation, differentiation, motility, adhesion, and survival [7,8,9]. Total and phosphorylated Src have been found to be increased in several human sarcoma tissues including high-grade osteosarcoma and various sarcoma cell lines (osteosarcoma, Ewing’s sarcoma, leiomyosarcoma, and rhabdomyosarcoma) [14]. In preclinical models and clinical studies, saracatinib modulates multiple key signaling pathways in cancer and inhibits osteoclast-mediated bone resorption [19,20,21,22,23,24,25,26,27,28]. Src and other genes that are involved in the Src pathway are activated in 95% of patients with osteosarcoma [14, 17]. ese data suggest that saracatinib may represent a promising therapy for the treatment of patients with recurrence of osteosarcoma

Patients and Methods

Results

Discussion

Conflicts of Interest