Phase III Randomized Trial of Hyperthermic Intraperitoneal Chemotherapy with Cisplatin and Sodium Thiosulfate in Epithelial Ovarian Cancer

The primary objective of this study is to assess the **efficacy** of hyperthermic intraperitoneal chemotherapy (HIPEC) in terms of disease-free survival (DFS) when combined with standard care, either Primary Debulking Surgery (PDS) or Interval Debulking Surgery (IDS), compared to standard care alone in patients with epithelial ovarian cancer, fallopian tube ovarian cancer, or peritoneal ovarian cancer. This evaluation is clinically relevant as it aims to determine whether the addition of HIPEC can improve DFS, potentially leading to better long-term outcomes for patients.

Secondary objectives include:

• Evaluating the efficacy of HIPEC in terms of overall survival (OS) when combined with standard care.
• Assessing the impact of HIPEC on safety.
• Determining the feasibility of adjuvant treatment post-surgery when HIPEC is used.
• Evaluating the trade-off between efficacy and morbidity using the Q-TWiST approach.
• Assessing the impact of HIPEC on quality of life.
• Exploratory objectives include evaluating the impact of HIPEC on the count of residual viable cells in abdominal drainage fluids and constituting a biobank for future translational research projects.

The clinical trial focuses on evaluating the efficacy of HIPEC treatment in combination with standard care for patients diagnosed with **epithelial ovarian cancer**, fallopian tube ovarian cancer, or peritoneal ovarian cancer. The study population comprises exclusively female participants, aged between 18 and 76 years, who are not considered part of a vulnerable population. Participants are required to have a histologically confirmed diagnosis of primary epithelial ovarian carcinoma, fallopian tube carcinoma, or peritoneal carcinoma, with a pre-therapeutic FIGO stage III. The trial does not include male subjects. The sponsor has not provided information regarding the total number of participants. Participants are expected to maintain adequate bone marrow and renal function, as well as a WHO Performance Status of 2 or less. Lifestyle factors such as diet and physical activity are not specified as part of the study criteria. The selection process involves ensuring that participants meet specific health criteria, including the absence of contraindications to the study medications and the ability to comply with the study protocol. The trial does not include individuals with contraindications to the study drugs or those unable to comply with the protocol requirements.

The clinical trial is a **Phase III randomized** study designed to evaluate the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with **epithelial ovarian cancer**, fallopian tube cancer, or peritoneal cancer. The trial aims to compare the disease-free survival (DFS) of patients receiving HIPEC combined with standard care, either primary debulking surgery (PDS) or interval debulking surgery (IDS), against those receiving standard care alone. The study is structured as a **double-blind, controlled** trial to ensure unbiased results. The estimated duration of the trial is from April 2019 to February 2032, with participant involvement expected to last until the end of the study or until early termination criteria are met.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and histological confirmation of the cancer type. Following successful screening, participants will be randomized to one of the treatment arms. Subsequent visits will include pre-operative assessments, the surgical procedure, and post-operative follow-ups to monitor recovery and treatment efficacy. Follow-up visits will be scheduled regularly to assess disease progression, adverse events, and overall survival. The end-of-study visit will occur at the conclusion of the participant's involvement, either due to completion of the study protocol or early termination.

Participants are expected to remain in the study for the duration of the treatment and follow-up period unless they meet conditions for early termination, such as significant adverse events, disease progression, or withdrawal of consent. The primary endpoint of the study is disease-free survival, while secondary endpoints include overall survival, adverse events, and quality of life assessments. The trial will also explore the impact of HIPEC on the feasibility of adjuvant treatment and the quality-adjusted time without symptoms of disease or toxicity. The study will utilize **cisplatin** and **sodium thiosulfate** as part of the treatment regimen, administered via intraperitoneal and intravenous routes, respectively.

The clinical trial involves the administration of **Sodium Thiosulfate**, a **solution for injection**. This experimental medication is administered **intravenously**. The dosage is calculated based on body surface area, with a maximum daily dose of **9 gm/m²**. The treatment period is limited to a maximum of one day. Sodium Thiosulfate is of chemical origin and is not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental treatment, the trial also includes the administration of **Cisplatin**, which serves as a comparator treatment. Cisplatin is administered via **intraperitoneal use**. The dosage is also based on body surface area, with a maximum daily dose of **100 mg/m²**. Similar to Sodium Thiosulfate, the treatment period for Cisplatin is restricted to one day. Cisplatin is a chemical compound and is not designed for pediatric formulations. Monitoring of participant adherence to the dosing regimen will be conducted to ensure compliance.

The efficacy of the clinical trial will be assessed primarily through **Disease-Free Survival (DFS)**. DFS is defined as the time interval between randomization and the occurrence of disease progression, relapse, or death from any cause. Progression and relapses will be evaluated according to GCIG criteria and ideally confirmed by a local tumor board. For patients who are alive without progression or relapse, data will be censored at the date of the last follow-up visit.

Secondary endpoints include **Overall Survival (OS)**, which will be measured as the time interval between randomization and death from any cause. For patients who are alive, data will be censored at the date of the last follow-up. Adverse events will be assessed according to NCI-CTCAE V5.0 throughout the treatment duration, from randomization to the end of treatment plus 30 days, excluding adverse events unequivocally related to the disease or its progression. Severe adverse events are defined as those of grade 3 or higher.

The impact of HIPEC on the feasibility of adjuvant treatment will be evaluated by examining the time interval between surgery and the start of adjuvant chemotherapy. A delay is considered if this interval exceeds 6 weeks, and reasons for any delay will be documented. The total number of chemotherapy courses (neo-adjuvant and adjuvant) will also be described, with reasons provided if the total is below the planned number of six courses.

Quality of life will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Score 30 (QLQ-C30) and the Quality of Life Questionnaire–Ovarian Cancer Module (QLQ-OV28). Additionally, exploratory endpoints include the count of residual viable cells in abdominal drainage fluids, evaluated by flow cytometry, and potential further research projects on the biobank of tumor and blood samples, contingent on additional funding.