Phase III Trial on Dose-Dense Carboplatin-Paclitaxel Regimen in Poor Prognostic Ovarian Cancer with Incomplete Debulking Surgery

The primary objective of the SALVOVAR trial is to demonstrate the **superiority** in terms of efficacy of a densification of the chemotherapy with the salvage weekly dose-dense carboplatin-paclitaxel regimen (experimental arm) compared to the continuation of the standard 3-weekly carboplatin-paclitaxel (control arm) in patients with poor prognostic ovarian cancer. This is characterized by poor chemosensitivity, an unfavorable KELIMTM score < 1.0, and disease not amenable to complete interval debulking surgery after 3 cycles of standard neo-adjuvant chemotherapy. The efficacy is defined with two co-primary endpoints: the percentage of patients operated with late complete debulking surgery after receiving 3 cycles of randomized chemotherapy and overall survival. These endpoints are clinically relevant as they aim to improve surgical outcomes and survival rates in a patient population with limited treatment options.

The secondary objectives include: - Comparing the efficacy of the salvage weekly dose-dense regimen with the standard regimen in terms of radiological response, progression-free survival, and the percentage of patients undergoing late complete debulking surgery. - Assessing the impact of the regimen adjustment on the rate of subsequent prescription of PARP inhibitors and its effect on survival. - Evaluating the impact of adding **bevacizumab** to chemotherapy on efficacy outcomes. - Comparing the safety profiles of the experimental and standard regimens, with or without bevacizumab, based on observed adverse events. - Comparing the quality of life and patient-reported outcomes between the two treatment arms. - Assessing the determinants of shared treatment decision-making regarding the use of bevacizumab, late debulking surgery, and maintenance treatments. - Evaluating the predictive value of tumor biomarkers involved in homologous recombination on efficacy outcomes. - Conducting cost-utility and cost-effectiveness evaluations of the experimental treatment in the French context. - Evaluating the financial sustainability of the experimental treatment for the payer in the French context.

The clinical trial involves a total of **20 participants** who are exclusively female, as the study focuses on patients with poor prognostic **ovarian cancers**. The participants are adults aged 18 years and older, with an advanced stage III or IV disease. The selection criteria required participants to have undergone 3 to 4 cycles of standard 3-weekly carboplatin-paclitaxel regimen in a first-line setting, characterized by a poor chemosensitivity and an unfavorable KELIMTM score of less than 1.0. Participants were also required to have adequate organ and bone marrow function, as well as adequate renal and liver functions, to be eligible for the weekly-dense chemotherapy regimen. The trial population was selected based on their histologically confirmed high-grade epithelial ovarian, primary peritoneal, or fallopian-tube carcinoma, and their ability to comply with the study protocol, including treatment and scheduled visits. Participants were required to provide written informed consent and be affiliated with a social insurance regime. The study does not include any vulnerable populations, and no specific lifestyle considerations such as diet or physical activity were highlighted as part of the selection criteria.

The clinical trial is designed as a **randomized**, phase III study to evaluate the efficacy of a dose-dense chemotherapy regimen in patients with poor prognostic ovarian cancer. The trial will compare the experimental arm, which involves a weekly dose-dense regimen of **carboplatin** and **paclitaxel**, against the control arm, which continues the standard 3-weekly regimen. The primary objective is to demonstrate the superiority of the experimental regimen in terms of efficacy, with co-primary endpoints being the percentage of patients undergoing late complete debulking surgery and overall survival. The trial is expected to commence recruitment on May 31, 2024, and conclude by December 31, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed high-grade epithelial ovarian cancer, advanced stage III or IV disease, and adequate organ function. Following randomization, participants will receive treatment over a maximum period of 64 weeks, with regular follow-up visits to monitor response and adverse events. The end-of-study visit will assess the final outcomes, including overall survival and progression-free survival.

The expected length of participant involvement is approximately 64 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The trial will employ a double-blind methodology to ensure unbiased results, with neither participants nor investigators aware of the treatment allocation. The study will also evaluate secondary endpoints such as overall response rate, quality of life, and the impact of shared decision-making on treatment outcomes. Participants will be monitored for adverse events according to the NCI Common Terminology Criteria for Adverse Events Version 5.0.

The clinical trial involves the administration of **PACLITAXEL**, an antineoplastic agent derived from a plant extract. It is provided as a **concentrate for solution for infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of 80 mg/m² and a total maximum dose of 720 mg/m² over a treatment period of 64 days. The administration route is intravenous infusion, and the frequency of administration is determined by the trial protocol.

**BEVACIZUMAB** is also utilized in the trial, functioning as a recombinant humanized anti-VEGF monoclonal antibody. It is available as a **concentrate for solution for infusion**. The dosing is weight-based, with a maximum daily dose of 15 mg/kg and a total maximum dose of 45 mg/kg over the same 64-day treatment period. This medication is administered intravenously, with the frequency of administration specified in the study protocol.

The trial includes **Filgrastim HEXAL 30 MU/0.5 ml**, a glycoprotein, provided as a **solution for injection or infusion in a pre-filled syringe**. The maximum daily dose is 30 million IU, with a total maximum dose of 540 million IU over 64 days. The administration can be either by injection or infusion, depending on the clinical requirements and protocol specifications.

**CARBOPLATIN** is another key component of the trial, classified as a second-generation platinum compound with broad antineoplastic properties. It is supplied as a **solution for infusion**. The maximum daily dose is 805 mg/ml, with a total maximum dose of 2415 mg/ml over the 64-day treatment period. The administration is via intravenous infusion, with dosing schedules outlined in the trial protocol.

All medications are administered under strict compliance monitoring to ensure adherence to the dosing schedules and to evaluate participant compliance. The trial aims to assess the efficacy of a dose-dense regimen compared to standard treatment in patients with poor prognostic ovarian cancer.

The efficacy of the clinical trial will be assessed using two co-primary endpoints: the percentage of patients who undergo late complete debulking surgery after receiving three cycles of randomized chemotherapy, and overall survival. The trial aims to demonstrate the superiority of a densified chemotherapy regimen, specifically the salvage weekly dose-dense carboplatin-paclitaxel regimen, compared to the standard 3-weekly carboplatin-paclitaxel regimen in patients with poor prognostic ovarian cancer. The efficacy is defined by an expected increase in the percentage of patients operated with late complete debulking surgery from 5% in the control arm to 20% in the experimental arm, and an improvement in overall survival by 49%, translating to an increase in median overall survival from 20 months in the control arm to 32.8 months in the experimental arm.

Secondary endpoints include overall response rate according to RECIST V1.1, progression-free survival, and the percentage of patients treated with a subsequent maintenance treatment with a PARP inhibitor. Additional assessments will include adverse events graded according to the NCI Common Terminology Criteria for Adverse Events Version 5.0, quality of life questionnaires, and the impact of shared decision-making on outcomes such as satisfaction with care and treatment adherence. The trial will also evaluate the percentage of patients with BRCA mutations and the financial impact over five years. These efficacy parameters will be measured and analyzed throughout the trial duration, with specific timepoints and methods aligned with clinical standards and trial protocols.