Sorafenib, Bevacizumab and Atezolizumab

Sorafenib by mouth every 12 hours, Days 1-21

Bevacizumab intravenously, every 3 weeks, Day 1

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).

This is a phase I/II study to evaluate the safety of combining intravenous (IV) atezolizumab and bevacizumab every three weeks, with daily oral cyclophosphamide and pharmacokinetic (PK)-guided sorafenib in children and adolescent and young adults (AYA) with relapsed or refractory solid malignancies (Part 1), and then evaluate the response rate of this combination in children, AYA with relapsed or refractory fibrolamellar carcinoma (FLC) and other rare solid malignancies (Part 2).

Primary Objectives Part 1 * To establish the safety associated with the administration of the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab in children and 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 Part 2 * To evaluate the response rate (CR+PR) of the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab in children and AYA with relapsed or refractory FLC following two cycles of therapy * To determine if the use of PK-guided sorafenib dosing to maintain a systemic exposure between 20 and 55 reduces the interpatient pharmacokinetic variability of sorafenib and the incidence of sorafenib- induced skin toxicities in children and AYA with relapsed or refractory FLC and other rare solid tumors Parts 1 & 2 * To determine if the combination of cyclophosphamide, PK-guided sorafenib and atezolizumab will result in increased intratumoral T-cell infiltration of CD8+C45RO+ cells between baseline and following two courses of therapy in pediatric 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.

Registro actualizado en ClinicalTrials.gov →

• Age: Patients must be < 30 years at the time of enrollment on study.
• Willingness to enroll on the St. Jude Molecular Analysis of Solid Tumors (MAST) study.
• Part 1: Patients with refractory or recurrent (relapsed) solid tumors accessible by biopsy for which there is no standard therapy are eligible.
• Biopsy accessible refractory or recurrent (relapsed) hepatocellular carcinoma
• Biopsy accessible refractory or recurrent (relapsed)or FL-HCC, DSRCT or non-CNS MRT.

Criterios de inclusión tal como figuran en el registro, recortados. La lista completa, con las exclusiones, está en el registro actualizado.