Safety and Efficacy of Cyclophosphamide, Sorafenib, Bevacizumab, and Atezolizumab in Pediatric Solid Tumor Patients

Exploratory Objectives (Parts 1 \& 2) * To determine the number of HCC and FLC xenografts that can be successfully established from children with relapsed or refractory disease (enrollment on MAST with biopsy for fresh tissue required) * To evaluate the immune cell infiltrates in children with relapsed or refractory solid tumors before and after two cycles of cyclophosphamide, sorafenib, bevacizumab and atezolizumab * To evaluate the number, type, specificity, repertoire, and activity of intratumoral T cells after two cycles of therapy, compared to baseline * To characterize changes in tumor associated macrophages (polarization) between baseline and after two cycles of cyclophosphamide, sorafenib, bevacizumab and atezolizumab * To measure changes in tumor mutational burden and mutation heterogeneity * To explore associations between T stem cell epigenetic signatures and response to treatment * To explore the association between baseline CD45RO+/CD8+ T-cell infiltration and PD-L1 expression and response to treatment * To characterize tumor heterogeneity and microenvironment using single-cell/nuclear RNA sequencing pre- and post-treatment * To longitudinally assess and quantify numerous metrics of quality of life (QoL), family distress and functional impairment for patients enrolled on ANGIOA and their primary caretakers * To qualitatively assess patient and family physical, emotional and psychosocial experiences prior to and after receipt of therapy on ANGIOA through semi-structured interviews * To assess the acceptability and feasibility of capturing patient/caregiver interview data at the time of enrollment and discontinuation on ANGIOA * To assess the feasibility of performing quantitative multiparametric mapping sequences in patients already undergoing MRI for staging purposes and explore the correlation between quantitative enhancement and other parameters and clinical response Part 1 (safety/tolerability): Children with relapsed or refractory solid tumors with biopsy accessible and evaluable disease will be treated with two courses of oral PK-guided sorafenib (starting area under the curve (AUC) target: 20-55 ug/ml/hr), oral cyclophosphamide (50 mg/m2/dose, daily (qd) x 21 days), IV bevacizumab (15 mg/kg/dose, every (q) 21 days) and IV atezolizumab (15 mg/kg \[max dose 1200 mg\] q 21 days). Tumor biopsies are required before starting treatment and after course two (Section 4.1). Biopsied tissue will be used for enrollment on MAST and to evaluate changes in T-cell infiltration. Sorafenib PK will be obtained and dose adjusted to target an AUC between 20 and 55 hr·µg/mL by Day 21 of C1. Tolerability will be defined after completion of Course 1. Part 2 will begin once the recommended phase 2 dose (RP2D) is determined. Part 2 (efficacy): Children and AYA with relapsed or refractory FLC will be treated with two courses of oral cyclophosphamide and sorafenib with IV bevacizumab and atezolizumab based on the RP2D from Part 1. Tumor response will be assessed after two courses according to immunologic and imaging criteria (Section 4.1). Eligible patients with hepatocellular (HCC), desmoplastic small round cell tumor (DSRCT) or non-central nervous system (CNS) malignant rhabdoid tumors (MRT) will be enrolled on separate strata but target accrual will be determined by patients with FLC.