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.