ANGIO-A: Study of Cyclophosphamide, Sorafenib, Bevacizumab, and Atezolizumab in Children and Young Adults with Solid Tumors

Brief Summary

This 2-part study evaluates the addition of the PD-L1 inhibitor atezolizumab to the antiangiogenic combination of low-dose cyclophosphamide, bevacizumab, and sorafenib.

Disordered angiogenesis helps tumor cells proliferate and survive, creating a microenvironment that helps the tumor evade immune system detection. Antiangiogenic agents can change the tumor microenvironment to be less immunosuppressive. Combined with immune checkpoint inhibitors, these agents can improve the efficacy of this immunotherapeutic approach.

St. Jude completed a phase 1 study showing that the antiangiogenic combination of low-dose cyclophosphamide, sorafenib, and bevacizumab was safe with signal of efficacy in multiple tumor types.

This is an ideal regimen to test in combination with atezolizumab due to:

• Its antiangiogenic nature
• Potential modulation of the immune microenvironment
• Tolerability of the combination of low-dose metronomic cyclophosphamide with sorafenib and bevacizumab
• Clinically meaningful responses

Primary Objectives

Part 1

• Establish the safety of combining cyclophosphamide, sorafenib, bevacizumab, and atezolizumab in patients with relapsed or refractory solid tumors
• Target sorafenib systemic exposure in combination with these 3 drugs

Part 2

• Evaluate the response from combining cyclophosphamide, sorafenib, bevacizumab, and atezolizumab in patients with relapsed or refractory hepatocellular carcinoma following 2 cycles of therapy
• Determine if the addition of PK-guided sorafenib dosing reduces the pharmacokinetic variability of sorafenib and the incidence of sorafenib-induced skin toxicities in patients

Eligibility Criteria

Part 1

• 1–30 years old
• Refractory or recurrent (relapsed) solid tumor for which there is no standard therapy
• Tumor accessible through biopsy

Part 2

• 1–30 years old
• Biopsy-accessible refractory or recurrent: hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, desmoplastic small round cell tumor, or non-CNS malignant rhabdoid tumor
• Karnofsky score of 50 or above for patients ages 16 and older
• Lansky score of 50 or above for patients younger than 16 years. Patients who are unable to walk because of paralysis, but can sit in a wheelchair, are considered ambulatory to assess the performance score.
• Unresectable tumors
• Adequate organ and bone marrow function
• Fully recovered from the acute toxic effects of chemotherapy, immunotherapy, surgery, or radiotherapy before entering the study
• A life expectancy of at least 8 weeks

Exclusion Criteria Include:

• Pregnant or breastfeeding
• Currently receiving other investigational drugs
• Tumor not safely accessible by biopsy
• Surgical procedures and serious or non-healing wounds in the 28 days before therapy begins
• Deep venous or arterial thrombosis (including pulmonary embolism) within 3 months before study entry

Study Site

St. Jude Children’s Research Hospital, Memphis, Tennessee

About this study

This study looks for effective treatments for childhood solid tumors that have returned after treatment or have never responded to therapy.

Some of these tumors may respond to a type of therapy called immunotherapy. This therapy helps the patient’s immune system see the tumor better and kill it. Disorganized blood vessels make it harder for immunotherapy to work. Immunotherapy may work better if we give medicines to change the blood vessels.

Atezolizumab is a form of immunotherapy. It is active in multiple cancer types. We already know that low-dose cyclophosphamide, bevacizumab, and sorafenib are safe. These medicines effectively target the blood vessels. We want to see how combining those 3 drugs with atezolizumab can help patients.

Purpose of this clinical trial

In Part 1 of this study, we will see if sorafenib, cyclophosphamide, bevacizumab, and atezolizumab can be given safely together without causing serious side effects.

Part 2 of the study will find out how well these medicines work in:

• Hepatocellular carcinoma
• Fibrolamellar carcinoma
• Desmoplastic small round cell tumors
• Malignant rhabdoid tumors

Eligibility overview

Part 1

• 1–30 years old
• Diagnosis of a solid tumor that has grown or has come back after treatment
• Ability to biopsy the tumor

Part 2

• 1–30 years old
• Diagnosis of:
  • Hepatocellular carcinoma that has grown or has come back after treatment
  • Fibrolamellar hepatocellular carcinoma
  • Desmoplastic small round cell tumor
  • A malignant rhabdoid tumor that is not in the central nervous system
• Ability to biopsy the tumor