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

NCT05468359 | Recruiting Phase 1 FDA Drug

• 1 other identifier: ANGIO-A
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 2

Brief 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 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

Conditions

Malignant Solid Tumor; Pediatric Cancer; Pediatric Solid Tumor; Fibrolamellar Carcinoma; Refractory Solid Tumor; Hepatocellular Carcinoma

Outcome Measures

Primary Outcomes (5)

• 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.

  At the end of cycle 2 (each cycle is 21 days)]

• 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.

  At the end of cycle 1 (each cycle is 21 days)]

• 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

  At the end of cycle 2 (each cycle is 21 days)]

• 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.

  At the end of cycle 1 (each cycle is 21 days)]

• Parts 1 & 2: Intratumoral T-cell infiltration of CD8+C45RO+ cells

  The number of participants whose tumors show an increase in the ratio of CD45RO+/CD3+ T cells of at least 27% OR who show an absolute increase in CD3+ cells from baseline to the end of cycle 2 (approximately 42 days from the start of therapy).

  At the end of cycle 2 (each cycle is 21 days)]

Secondary Outcomes (7)

• Part 1:Response rate of relapsed or refractory solid tumors

  At the end of cycle 2 (each cycle is 21 days)]

• Part 2: Response rate of relapsed or refractory fibrolamellar carcinoma, desmoplastic small round cell tumor, malignant rhabdoid tumor

  At the end of cycle 2 (each cycle is 21 days)]

• Resection rate of liver tumors

  At the end of cycle 1 (each cycle is 21 days)]

• Progression Free Survival

  At the end of cycle 2 (each cycle is 21 days

• Event Free Survival

  At the end of cycle 2 (each cycle is 21 days

Study Arms (1)

Treatment

OTHER

All participants will receive Atezolizumab, Bevacizumab,Sorafenib and cyclophosphamide until maximum tolerated dose is reached.Tolerability will be defined after completion of Course 1. Part 2 will begin once the recommended phase 2 dose (RP2D) is determined.

Drug: Atezolizumab; Drug: Sorafenib; Drug: Bevacizumab; Drug: Cyclophosphamide

Interventions

Cyclophosphamide DRUG

Low-dose cyclophosphamide by mouth once daily, Days 1-21

Also known as: Cytoxan(R)

Treatment

Atezolizumab DRUG

Atezolizumab intravenously, every 3 weeks, Day 1

Also known as: TECENTRIQ®

Treatment

Sorafenib DRUG

Sorafenib by mouth every 12 hours, Days 1-21

Also known as: BAY-43-9006, Nexavar(R)

Treatment

Bevacizumab DRUG

Bevacizumab intravenously, every 3 weeks, Day 1

Also known as: rhuMab VEGF, Avastin(R)

Treatment

Eligibility Criteria

• Age: Up to 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• Part 2: Patients with one of the following diagnoses:
• Biopsy accessible refractory or recurrent (relapsed) hepatocellular carcinoma
• Biopsy accessible refractory or recurrent (relapsed)or FL-HCC, DSRCT or non-CNS MRT.
• Performance level: Karnofsky \> 50 for patients \> 16 years of age and Lansky \> 50 for patients \< 16 years of age (See Appendix III). Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Disease status: Patients must tumors that are unresectable and have either measurable or evaluable disease that is accessible by biopsy
• Organ function: Must have adequate organ and bone marrow function as defined by the following parameters:
• Patients with solid tumor not metastatic to bone marrow:
• Peripheral absolute neutrophil count (ANC) \>1,000/mm3
• Platelet count \> 75,000/mm3 (no transfusion within 7 days of enrollment)
• Hemoglobin \> 8 g/dL (with or without support)
• Patients with solid tumor metastatic to bone marrow will be eligible for study but not evaluable for hematologic toxicity. These patients must not be known to be refractory to red cell or platelet transfusions. At least 2 of every cohort of 3 patients must be evaluable for hematologic toxicity. If dose limiting hematologic toxicity is observed at any dose level, all subsequent patients enrolled must be evaluable for hematologic toxicity.

You may not qualify if:

• 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
• Inability or unwillingness of research participant or legal guardian / representative to give written informed consent.
• Surgical procedures and serious or non-healing wounds: patients with a documented, chronic non-healing wound, ulcer, or bone fracture or history of a major surgical procedure or significant traumatic injury within 28 days prior to beginning therapy are excluded due to preclinical evidence supporting the potential for delayed wound healing.
• Minor surgical procedures for minimally invasive biopsies will be allowed. For minor surgeries, the wound must be healed, and 7 days elapsed since surgery. For procedures such as the placement of an indwelling IV catheter, it is recommended that bevacizumab be postponed for at least 24 hours after the procedure.
• Thrombosis: Patients must not have a deep venous or arterial thrombosis (including pulmonary embolism) within the last three months prior to study entry and must not have a known thrombophilic condition (i.e., protein S, protein C or antithrombin III deficiency, Factor V Leiden, Factor II G20210A mutation, homocysteinemia or antiphospholipid antibody syndrome).

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead

Study Sites (2)

Methodist Le Bonheur Healthcare

Germantown, Tennessee, 38138, United States

WITHDRAWN

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

RECRUITING

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Neoplasms; Fibrolamellar hepatocellular carcinoma

Interventions

atezolizumab; Sorafenib; Bevacizumab; Cyclophosphamide

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Study Officials

• Jessica Gartrell, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jessica Gartrell, MD

CONTACT

866-278-5833; referralino@stjude.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2022
• First Posted: July 21, 2022
• Study Start: November 7, 2022
• Primary Completion (Estimated): June 1, 2032
• Study Completion (Estimated): June 1, 2037
• Last Updated: March 16, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be made available at the time of article publication.
• Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

Locations

US (2)