1 INTRODUCTION
Ewing sarcoma and osteosarcoma are aggressive malignancies of bone and/or soft tissue which most commonly affect adolescents and young adults. Patients with relapsed Ewing sarcoma likewise fare poorly [1-4]. Outcomes for patients with relapsed osteosarcoma are poor, with one analysis reporting 12% event-free survival (EFS) at 4 months [5]. Given these outcomes, new treatment approaches are needed.
Recently, there has been tremendous interest in a range of multitargeted tyrosine kinase inhibitors (mTKIs) in patients with bone sarcoma. Cabozantinib is an oral small molecule potent mTKI of proinavsive receptor tyrosine kinases (RTKs), most notably VEGFR-2 and MET, important mediators of tumor growth and angiogenesis. [6, 7] [6, 7] [6, 7] [11, 12] Ewing sarcoma and osteosarcoma both over-express MET and this expression is associated with an aggressive phenotype and poor prognosis [8-10]. The pediatric phase 1 study of cabozantinib identified 40 mg/m2/day continuous dosing as the recommended phase 2 dose [11]. Importantly, a European phase 2 single agent study of cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma reached its primary efficacy endpoint in both the Ewing sarcoma and osteosarcoma cohorts. Specifically, single agent cabozantinib yielded an objective response in 25.6% of Ewing sarcoma patients and 33.3% of osteosarcoma patients had 6-month non-progression[12]. Efforts to build upon this activity have been limited. Preclinical studies have demonstrated that targeting proangiogenic mechanisms in combination with cytotoxic chemotherapy may overcome chemoresistance and inhibit growth of sarcomas [13]. Prior studies in adult patients with high-grade gliomas and advanced pancreatic cancer combined cabozantinib with other cytotoxic agents and/or radiotherapy with acceptable adverse effect profiles [14, 15].
Cyclophosphamide and topotecan have shown activity against Ewing sarcoma and osteosarcoma in both phase 1 and phase 2 trials. In initial testing, the recommended phase 2 dose was cyclophosphamide 250mg/m2 and topotecan 0.75mg/m2each IV on Days 1-5 of a 21-day cycle. This combination was overall well tolerated with primarily hematologic toxicities. In the phase 1 study, 1 (20%) patient with osteosarcoma had partial response and 2 (40%) had stable disease, while 3 (60%) of Ewing sarcoma patients had stable disease [16]. In a phase 2 study, 36% of patients with Ewing sarcoma and 11% of patients with osteosarcoma had objective responses [17].
While cabozantinib and separately topotecan/cyclophosphamide are active in patients with Ewing sarcoma and osteosarcoma, they have not previously been studied in combination. In our trial, we aimed to determine the safety and toxicity of oral cabozantinib in combination with IV topotecan and cyclophosphamide, and to select the recommended phase 2 doses (RP2D) and schedules for this combination in pediatric patients with relapsed or refractory Ewing sarcoma or osteosarcoma.