Combining cyclophosphamide, sorafenib, bevacizumab, and atezolizumab for children and young adults with relapsed solid tumors

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

This will test whether giving atezolizumab and bevacizumab every three weeks together with daily cyclophosphamide and dose‑adjusted sorafenib is safe and can shrink relapsed or hard‑to‑treat solid tumors in children and young adults, including fibrolamellar carcinoma.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 64 (estimated)
• Ages: N/A to 30 Years
• Sex: All
• Sponsor: St. Jude Children's Research Hospital (Academic / other)
• Drugs / interventions: bevacizumab, chemotherapy, immunotherapy, atezolizumab, cyclophosphamide
• Locations: 2 sites (Germantown, Tennessee and 1 other locations)
• Trial ID: NCT05468359 on ClinicalTrials.gov

What this trial studies

This is a Phase 1/2 trial that first tests safety and pharmacokinetic targeting of sorafenib when given with cyclophosphamide, bevacizumab, and atezolizumab in children and adolescents/young adults with relapsed or refractory solid tumors. Part 1 focuses on safety and whether sorafenib systemic exposure can be reliably targeted by Day 21 of cycle 1; Part 2 measures response rate in fibrolamellar carcinoma and other rare solid malignancies. Treatment consists of IV atezolizumab and bevacizumab every three weeks, daily oral cyclophosphamide, and PK‑guided oral sorafenib, with required tumor biopsy/enrollment on the St. Jude MAST program for translational studies. Extensive correlative work includes pre/post treatment tumor immunology, single‑cell sequencing, tumor mutational analyses, and longitudinal quality‑of‑life and family distress assessments.

Who should consider this trial

Good fit: Ideal candidates are patients under 30 with relapsed or refractory, biopsy‑accessible solid tumors (including fibrolamellar carcinoma and other rare tumors), with Karnofsky/Lansky performance scores >50 and no curative standard options, who are willing to enroll on the St. Jude MAST program.

Not a fit: Patients who cannot undergo required biopsies, have poor performance status (<50), significant organ dysfunction, rapidly progressing disease that precludes protocol therapy, or who have effective standard treatment options are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the combination could produce tumor shrinkage or disease control in children and young adults with relapsed or refractory solid tumors and identify immune and molecular markers to guide future care.

How similar studies have performed: PD‑L1 blockade combined with bevacizumab has shown benefit in adult hepatocellular carcinoma and sorafenib has activity in liver tumors, but this specific four‑drug combination and its use in pediatric relapsed solid tumors is largely novel and unproven.

Eligibility criteria

Inclusion Criteria:

* 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.
* Adequate renal function defined as serum creatinine based on age as shown in Table 1, or creatinine clearance or radioisotope GFR 50 ml/min/1.73m2 (GFR 40 ml/min/1.73m2 if \< 2 years of age).
* Adequate hepatic function defined as total bilirubin \< 5x upper limit of normal (ULN) and AST/ALT \< 3 x ULN for age.
* Adequate cardiac function defined as shortening fraction \> 28% OR ejection fraction of ≥ 47% by echocardiogram.
* Adequate blood clotting defined as PT/PTT \< 1.2 x ULN without factor replacement products for 7 days
* Females of childbearing potential and males able to father a child must be willing to practice acceptable methods of birth control to prevent pregnancy during the study and for at least 5 months after last dose of therapy.
* Patients must have fully recovered from the acute toxic effects of chemotherapy, immunotherapy, surgery, or radiotherapy prior to entering this study:
* Myelosuppressive chemotherapy: Patient has not received myelosuppressive chemotherapy within 1 weeks of enrollment onto this study (within 2 weeks of estimated therapy start date) (4 weeks if prior nitrosourea).
* Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim.
* Biologic (anti-neoplastic agent): At least 7 days must have elapsed since completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur.
* Monoclonal antibodies: At least 14 days (at least 21 days from therapy start date) must have elapsed since the completion of therapy with a monoclonal antibody.
* Radiotherapy: At least 1 week (2 weeks from estimated therapy start date) must have elapsed since any irradiation; at least 5 weeks (at least 6 weeks from estimated therapy start date) must have elapsed since craniospinal RT or substantial bone marrow irradiation.
* Chemoembolization: at least 21 days (28 days from estimated therapy start date) must have elapsed since the completion of chemoembolization
* Radioembolization: at least 21 days (28 days from estimated therapy start date) must have elapsed since the completion of radioembolization
* Cardiac disease or hypertension: Patients must not have a history of myocardial - infarction, severe or unstable angina, or severe peripheral vascular disease. Hypertension must be well controlled on stable doses of medication for at least two weeks.
* Female participant who is post-monarchal must have a negative urine or serum pregnancy test.
* Life expectancy of at least 8 weeks

Exclusion Criteria:

* 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).

Where this trial is running

Germantown, Tennessee and 1 other locations

• Methodist Le Bonheur Healthcare — Germantown, Tennessee, United States (Withdrawn)
• St. Jude Children's Research Hospital — Memphis, Tennessee, United States (Recruiting)

Study contacts

• Principal investigator: Jessica Gartrell, MD — St. Jude Children's Research Hospital
• Study coordinator: Jessica Gartrell, MD

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