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

Hepatocellular Carcinoma Clinical Trial

Official title: ANGIO-A: Safety and Tolerability of Oral Cyclophosphamide and Sorafenib With Intravenous Bevacizumab With the Addition of Atezolizumab in Pediatric Solid Tumor Patients

Status Recruiting

Clinical Trial Summary

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 hepatocellular carcinoma (HCC) 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 HCC 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 HCC 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.

Secondary Objectives

Part 1

• To describe the response rate (CR+PR) of the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab in children and AYA with relapsed or refractory solid tumors following two cycles of therapy

Part 2

• To describe the response rate (CR+PR) of the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab in children and AYA with relapsed or refractory fibrolamellar carcinoma, desmoplastic small round cell tumor, malignant rhabdoid tumor, and other rare solid tumors following two cycles of therapy

Parts 1&2

• To describe the number of children with liver tumors, initially judged unresectable at diagnosis, that can have their primary tumor resected after treatment with oral cyclophosphamide and sorafenib with intravenous bevacizumab and atezolizumab

• To describe changes in immune cells in the peripheral blood at periodic times before and after treatment with this combination chemoimmunotherapy

• To describe the PFS, EFS, and OS in patients treated with the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab, and atezolizumab in patients with relapsed or refractory HCC, DSRCT, MRT, FL-HCC and other rare solid tumors

Clinical Trial Description

Exploratory Objectives (Parts 1 & 2)

• To determine the number of HCC and FL-HCC xenografts that can be successfully established from children with relapsed or refractory HCC (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 evaluate the correlation of CEUS imaging characteristics with the expression of CD34 in biopsy samples

• To establish HCC organoid and spheroid ("HCCoid") cultures from patient tumor samples and study the correlation between the biological features of the HCCoids and the progression of their parental tumors in patients

• To study the interaction between HCCoids and liver cells from different developmental stages to understand the contribution of the developmental microenvironment to HCC development

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 HCC 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 Fibrolamellar Carcinoma (FL-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 HCC. ;

Related Conditions & MeSH terms

• Carcinoma
• Fibrolamellar Carcinoma
• Hepatocellular Carcinoma
• Malignant Solid Tumor
• Neoplasms
• Pediatric Cancer
• Pediatric Solid Tumor
• Refractory Solid Tumor

• NCT number: NCT05468359
• Study type: Interventional
• Source: St. Jude Children's Research Hospital
• Contact: Jessica Gartrell, MD
• Phone: 866-278-5833
• Email: referralino@stjude.org
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: November 7, 2022
• Completion date: June 2037