Evaluation of Cisplatin-Based Regimens and Drug Combinations in Pediatric Hepatoblastoma and Hepatocellular Carcinoma: A Multicenter Clinical Trial

The primary objective of the Paediatric Hepatic International Tumour Trial (PHITT) is to evaluate treatment outcomes and collect biological samples for toxicity studies in various risk groups of patients with **hepatoblastoma** and **hepatocellular carcinoma**. This includes assessing the efficacy of different chemotherapy regimens and surgical interventions across defined risk categories, such as very low-risk, low-risk, intermediate-risk, high-risk, resected, and unresected groups. The clinical relevance lies in optimizing treatment protocols to improve survival rates and reduce treatment-related toxicity in pediatric patients.

Secondary objectives include:

• Reporting outcomes such as event-free survival (EFS), overall survival (OS), and treatment-related toxicity across all patient groups.
• Validating a new global risk stratification model defined by the Children's Hepatic Tumours International Collaboration (CHIC).
• Evaluating clinically relevant factors, including the development of a comprehensive panel of diagnostic and prognostic biomarkers, determining biological differences between pediatric and adult hepatocellular carcinoma, and developing genomic or biomarker analyses to predict chemotherapy-related toxicity risks in children.
• Establishing a collection of clinically and pathologically annotated biological samples.

The clinical trial involves a total of **157 participants** diagnosed with **Hepatoblastoma** or **Hepatocellular Carcinoma**. The study population includes both male and female subjects, with an age range of up to 30 years. Participants were selected based on a clinical or histological diagnosis of the specified conditions, with additional criteria ensuring adequate cardiac, renal, and hematological function. The trial includes a vulnerable population, indicating that some participants may have additional health considerations. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The selection process adhered to specific inclusion criteria, such as the requirement for written informed consent and, for females of child-bearing potential, a negative pregnancy test prior to trial entry. The trial aims to evaluate various treatment protocols across different risk groups, with the primary objective of collecting samples for biological and toxicity studies.

The clinical trial is designed to evaluate the efficacy and safety of various treatment regimens for **hepatoblastoma** and **hepatocellular carcinoma**. This is a randomized, double-blind, controlled trial with an exploratory and confirmatory phase III classification. The trial is expected to commence recruitment on October 17, 2024, and conclude by December 31, 2027. Participants will be stratified into different risk groups (A to F) based on their diagnosis and treatment needs, with each group receiving specific treatment protocols. The primary objective is to assess event-free survival, while secondary endpoints include overall survival, failure-free survival, and toxicity assessments.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit involves screening to confirm eligibility based on criteria such as age, cardiac function, and renal function. Participants will undergo regular follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will evaluate the final outcomes and collect any remaining data. The expected length of participant involvement varies by treatment group, with the maximum treatment period ranging from 12 to 23 months, depending on the specific regimen.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in the participant's best interest. The trial will utilize a range of chemotherapeutic agents, including **cisplatin**, **carboplatin**, **doxorubicin hydrochloride**, **fluorouracil**, **etoposide**, **sorafenib**, **irinotecan**, **oxaliplatin**, **vincristine sulfate**, and **gemcitabine hydrochloride**, administered via infusion or oral routes as appropriate. The trial aims to provide valuable insights into optimizing treatment strategies for these challenging conditions.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Cisplatin** is provided as a solution for infusion, with a maximum daily dose of 100 mg/m² and a total dose limit of 600 mg/m² over a treatment period of up to 12 weeks. The administration route is via infusion.

**Carboplatin** is administered as a concentrate for solution for infusion. The maximum daily dose is 500 mg/m², with a total dose limit of 3900 mg/m² over a maximum treatment period of 18 weeks. The administration is conducted through infusion.

**Doxorubicin Hydrochloride** is available as a solution for infusion, with a maximum daily dose of 30 mg/m² and a total dose limit of 300 mg/m² over a treatment period of up to 23 weeks. The route of administration is infusion.

**Fluorouracil** is administered as a solution for injection or infusion, with a maximum daily dose of 600 mg/m² and a total dose limit of 3600 mg/m² over a treatment period of up to 18 weeks. The administration can be via intravenous bolus injection or IV infusion.

**Etoposide** is provided as a solution for infusion, with a maximum daily dose of 200 mg/m² and a total dose limit of 1200 mg/m² over a treatment period of up to 14 weeks. The administration is conducted through infusion.

**Sorafenib** is administered in the form of film-coated tablets, with a maximum daily dose of 300 mg/m² and a total dose limit of 32400 mg/m² over a treatment period of up to 18 weeks. The route of administration is oral.

**Irinotecan** is available as a concentrate for solution for infusion, with a maximum daily dose of 50 mg/m² and a total dose limit of 300 mg/m² over a treatment period of up to 14 weeks. The administration is conducted through infusion.

**Oxaliplatin** is provided as a solution for infusion, with a maximum daily dose of 100 mg/m² and a total dose limit of 400 mg/m² over a treatment period of up to 14 weeks. The administration is conducted through infusion.

**Vincristine Sulfate** is administered as an injection, with a maximum daily dose of 2 mg and a total dose limit of 12 mg over a treatment period of up to 15 weeks. The administration can be via intravenous bolus injection or IV infusion.

**Gemcitabine Hydrochloride** is available as a solution for infusion, with a maximum daily dose of 1000 mg/m² and a total dose limit of 4000 mg/m² over a treatment period of up to 14 weeks. The administration is conducted through infusion.

All medications are of chemical origin and are not formulated for pediatric use. Participant compliance is monitored through scheduled dosing and infusion sessions, ensuring adherence to the prescribed treatment regimens. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The primary aim is to evaluate the efficacy and safety of these experimental medications in the treatment of various risk groups of hepatoblastoma and hepatocellular carcinoma.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Event Free Survival (EFS)**, which is defined as the time from randomization or registration into the trial for non-randomized patients to the first failure event. This includes progression of existing disease, occurrence of disease at new sites, death from any cause prior to disease progression, and diagnosis of a second malignant neoplasm. For patients with hepatocellular carcinoma (HCC), response is defined as complete or partial according to RECIST version 1.1 criteria, assessed after specific cycles of treatment.

Secondary endpoints include Failure-free survival (FFS), Overall survival (OS), and toxicity assessments. FFS is defined similarly to EFS with the addition of failure to proceed to resection. OS is defined as the time from randomization to death from any cause, with patients who have not died being censored at their last follow-up date. Toxicity will be recorded and categorized using the Common Terminology Criteria for Adverse Events (CTCAE), with specific attention to chemotherapy-related cardiac, nephro-, and oto-toxicity. Hearing loss will be measured using the SIOP Boston Scale for oto-toxicity at the end of treatment and during follow-up.

Additional assessments include Best Response, defined as Complete Response (CR) and Progressive Response (PR), based on radiological response and AFP decline, measured throughout the treatment period and follow-up. Surgical resectability will also be evaluated, defined as complete resection, partial resection, or transplant following randomization or enrollment for non-randomized patients.