(P 528) SAFETY AND TOLERABILITY OF ORAL CYCLOPHOSPHAMIDE AND SORAFENIB WITH INTRAVENOUS BEVACIZUMAB WITH THE ADDITION OF ATEZOLIZUMAB IN PEDIATRIC SOLID TUMOR PATIENTS

Objective: There is a growing body of evidence that VEGF plays a pivotal role in creating an immunosuppressive microenvironment and that increased expression of PD-L1 is a mechanism of resistance to anti-angiogenic agents.

This is a Phase 1/2 study evaluating the safety and efficacy of the combination of low dose cyclophosphamide with atezolizumab, bevacizumab, and pharmacokinetically (PK) guided sorafenib in patients with pediatric recurrent, refractory solid tumors. The primary objectives are as follows.

•To establish the safety associated with the administration of the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab in children and adolescents/young adults (AYA) with relapsed or refractory solid tumors

•To determine if sorafenib systemic exposure can be successfully targeted to an AUC between 20 and 55 hr·µg/mL by Day 21 of cycle 1 in 60% of evaluable patients, when given in combination with cyclophosphamide, bevacizumab, and atezolizumab in children and AYA with relapsed or refractory solid tumors

•To determine if the combination of cyclophosphamide, PK-guided sorafenib and atezolizumab will result in increased intratumoral T-cell infiltration of CD45RO+ cells between baseline and following two courses of therapy in children and AYA with relapsed or refractory solid tumors following two cycles of therapy

•To characterize the pharmacokinetics of atezolizumab in combination with cyclophosphamide, PK-guided sorafenib and bevacizumab in children and AYA with relapsed or refractory solid tumors

•To assess the feasibility of performing contrast-enhanced ultrasound and explore the correlation between quantitative CEUS parameters and clinical response.

Methods: Patients between the ages of 1-30 years with biopsy-accessible, recurrent or refractory solid tumors with acceptable organ status will be eligible for the study. In addition to standard labs and imaging studies, patients will have a tumor biopsy in conjunction with a contrast-enhanced ultrasound prior to the initiation of study treatment. Treatment will consist of: atezolizumab intravenously, every 3 weeks, Day 1, bevacizumab intravenously, every 3 weeks, Day 1, low-dose cyclophosphamide by mouth once daily, Days 1-21, and sorafenib by mouth every 12 hours, Days 1-21 (Table 1). PK samples of sorafenib will be drawn to achieve a target AUC between 20-55 hr·µg/ml. Each treatment cycle will be 21 days. After completion of two cycles, imaging and the biopsy will be repeated. The ratio of CD45RO+/CD3+ of cells will be calculated, in addition to the total number of CD3+ cells. Treatment will continue if there is at least stable disease and/or an increase in immune cell infiltrate (Figure 1).

Results: .........N/A

Conclusion: ...........N/A