Evaluation of Bevacizumab Dose Equivalence in First-Line Treatment of Ovarian, Fallopian Tube, and Peritoneal Carcinomas with Olaparib, Carboplatin, and Paclitaxel

The primary objective of this study is to verify the hypothesis that there is no difference in survival to progression for patients with **ovarian cancer** enrolled in the standard 15 mg and low 7.5 mg dose arms of **bevacizumab** as part of their treatment. This objective is clinically relevant as it aims to determine the optimal dosing strategy for bevacizumab, potentially impacting treatment protocols and patient outcomes in ovarian cancer therapy.

The secondary objective is to assess the net clinical effect of the efficacy endpoints, broken down into individual events such as death, disease progression, and the need for subsequent therapy, in relation to safety, defined as the incidence of adverse events (AE/SAE/AESI). This evaluation is crucial for understanding the balance between treatment efficacy and safety, thereby guiding clinical decision-making and improving patient care.

The clinical trial involves a study population consisting exclusively of **female** participants diagnosed with **ovarian cancer**, fallopian tube cancer, or peritoneal carcinoma. The age range of the participants is 18 years and older. The trial does not include a vulnerable population. Participants were selected based on specific inclusion criteria, such as having undergone cytoreductive surgery within 8 weeks prior to study inclusion and having a histological diagnosis of advanced high-grade ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. The trial requires participants to have a general performance status of 0-1 according to the ECOG classification and to meet specific blood morphology and coagulation indicators. Lifestyle considerations include the commitment to abstain from heterosexual intercourse or use two effective methods of contraception, as well as refraining from ova donation and cryopreservation during the study and for 6 months after. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a multi-centre, four-arm, **randomized**, **double-blind** study designed to assess the dose equivalence of **bevacizumab** in first-line therapy for patients with **ovarian cancer**, fallopian tube cancer, or peritoneal carcinoma. The primary objective is to verify the hypothesis that there is no difference in survival to progression between patients receiving the standard 15 mg and low 7.5 mg dose arms of bevacizumab. The trial is expected to commence recruitment on May 1, 2024, and conclude by April 30, 2029. Participants will be involved in the study for a maximum treatment period of 76 weeks, depending on the treatment arm.

The trial design includes an initial screening visit to confirm eligibility based on specific inclusion criteria, such as age ≥ 18 years, recent cytoreductive surgery, and adequate liver and kidney function. Participants must also provide informed consent and demonstrate a willingness to comply with the study protocol. Following the screening, eligible participants will be randomized into one of the four treatment arms. The study involves multiple follow-up visits to monitor treatment response and adverse events, with the primary endpoints being the Objective Response Rate (ORR) and Progression-Free Survival (PFS). Secondary endpoints include the frequency of adverse events, quality of life assessments, and time to subsequent therapy.

Participants will attend regular study visits throughout the treatment period, during which clinical assessments, laboratory tests, and imaging studies will be conducted to evaluate treatment efficacy and safety. The end-of-study visit will occur after the completion of the adjuvant treatment phase, approximately four weeks post-treatment, to assess the final treatment response and collect data on any remaining adverse events. Conditions that may lead to early termination from the study include significant protocol deviations, withdrawal of consent, or the occurrence of severe adverse events that compromise participant safety. The study is conducted in accordance with ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of several **experimental medications** and standard treatments to evaluate their efficacy in the treatment of ovarian cancer. **Olaparib** is utilized in this study as a film-coated tablet, with an active substance origin classified as chemical. The maximum daily dose of olaparib is 600 mg, administered orally, with a total treatment period of up to 36 weeks. The medication is provided in a non-paediatric formulation and is categorized as a cytostatic agent.

Another formulation of **olaparib** is also included in the trial, with a maximum daily dose of 400 mg, administered orally. This formulation shares the same chemical origin and treatment period of 36 weeks as the previous olaparib formulation, and it is also classified as a cytostatic agent.

**Carboplatin** is administered as a solution for infusion, with a chemical origin. The maximum daily dose is 6 mg/ml, and the treatment period is limited to 6 weeks. This medication is also categorized as a cytostatic agent and is not formulated for paediatric use.

**Bevacizumab** is included in the trial as a solution for infusion, with a protein origin classified as "Protein - Other." The maximum daily dose is 15 mg/kg, with a treatment period extending up to 76 weeks. Bevacizumab is categorized as a monoclonal antibody and is not intended for paediatric use.

**Paclitaxel** is administered as a solution for injection, with a chemical origin. The maximum daily dose is 175 mg/m², and the treatment period is 6 weeks. This medication is classified as a cytostatic agent and is not formulated for paediatric use.

The trial also includes a comparator treatment with **bevacizumab** in a different formulation, maintaining the same dosage and treatment period as the previously mentioned bevacizumab. This formulation is also a solution for infusion, with a protein origin classified as "Protein - Other," and is categorized as a monoclonal antibody.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)** to treatment, defined as the proportion of patients with a complete or partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) within 4 weeks after the completion of the adjuvant treatment phase. Additionally, **Progression-Free Survival (PFS)** will be evaluated, defined as the time from randomization to disease progression or recurrence according to RECIST v.1.1, or all-cause death, whichever occurs first.

Secondary endpoints will include the frequency of adverse events (AE), serious adverse events (SAE), and adverse events of special interest (AESI). The study will also measure death from any cause, ORR based on the best overall response (BOR) over the entire treatment period according to RECIST v.1.1, and the time from the start of first-line chemotherapy to the start of first subsequent therapy (TFST). Furthermore, an analysis of the study participants' quality of life will be conducted using standardized quality of life questionnaires QLQ-C30 and QLQ-OV28 from the European Organisation for Research and Treatment of Cancer.