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.
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 FLC, HCC, 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 FLC, DSRCT, MRT, HCC and other rare solid tumors
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.
Diagnosis
Part 1: Patients with refractory or recurrent (relapsed) solid tumors accessible by biopsy for which there is no standard therapy are eligible.
Pregnant or breastfeeding.
Currently receiving other investigational drugs.
Unwilling or unable to comply with the safety monitoring requirements of this protocol.
Tumor not safely accessible by biopsy
Single group
Atezolizumab
DrugAtezolizumab intravenously, every 3 weeks, Day 1
Sorafenib
DrugSorafenib by mouth every 12 hours, Days 1-21
Bevacizumab
DrugBevacizumab intravenously, every 3 weeks, Day 1
Cyclophosphamide
DrugLow-dose cyclophosphamide by mouth once daily, Days 1-21
Part 1: Recommended phase 2 doses (RP2Ds)
The number of participants who develop a dose limiting toxicity within the first two cycles of therapy that are at least possibly, probably or definitely attributable to atezolizumab, bevacizumab, sorafenib or cyclophosphamide.
PK measures of Sorafenib
The number of participants exhibiting a sorafenib exposure (steady-state AUC0-12h) between 20 and 55 hr·µg/mL by Day 21 of cycle 1.
Part 2: Response rate
The number of participants with relapsed or refractory HCC whose tumors show a response (CR+PR) after 2 cycles of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab
PK measure of sorafenib
The number of participants who have a sorafenib systemic exposure between 20 and 55 who experience sorafenib-induced skin toxicity compared to the number of participants who have a systemic sorafenib exposure outside of the 20-55 range who experience sorafenib-induced skin toxicity.
Part 1:Response rate of relapsed or refractory solid tumors
The number of participants with relapsed or refractory solid tumors whose tumors have a response (CR or PR) after two cycles of the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab.
Part 2: Response rate of relapsed or refractory fibrolamellar carcinoma, desmoplastic small round cell tumor, malignant rhabdoid tumor
The number of participants with relapsed or refractory fibrolamellar carcinoma, desmoplastic small round cell tumor, malignant rhabdoid tumor, and other rare solid tumors whose tumors have a response (CR or PR) after two cycles of the combination of cyclophosphamide, PK-guided sorafenib, bevacizumab and atezolizumab.
Resection rate of liver tumors
The number of participants with liver tumors, initially judged relapsed or refractory at diagnosis, that can have their primary tumor resected after treatment with oral cyclophosphamide and sorafenib with intravenous bevacizumab and atezolizumab.
Progression Free Survival
The PFS of 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.
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