The protocol was structured according to the SPIRIT reporting guidelines (SPIRIT 2013 Checklist) [14].
Ethics statement
This trial has been prospectively registered at the EUCT number: 2023–509659-15–00, 15/07/2024. The trial protocol has been reviewed by the European Medicines Agency (reference number: 2023–509659-15–00, 15/07/2024). In compliance with the Declaration of Helsinki of 1964, as revised in 2013, the International Conference of Harmonization Guidelines for Good Clinical Practice, and the guidelines of local ethics committees, written informed permission will be obtained from all subjects when patients are enrolled in the study [15].
Study population
The study will include 332 women with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer at FIGO stage III or IV who had undergone neoadjuvant chemotherapy and interval debulking surgery, regardless of residual disease status. Randomization will be performed using an Interactive Web Response System (IWRS), which will allocate participants into four study arms based on predefined stratification factors. This study is designed as a double-blind clinical trial, meaning that both the participants and the investigators involved in treatment administration and outcome assessment will be unaware of the treatment assignments. Blinding is maintained to minimize bias in the evaluation of efficacy and safety outcomes. Unblinding of a participant’s treatment allocation will be permissible only in exceptional circumstances when knowledge of the assigned intervention is essential for the clinical management of the patient, such as in the case of a serious adverse event where appropriate medical care requires this information. In such situations, unblinding must be approved and documented by the principal investigator and conducted through the Interactive Web Response System (IWRS), which maintains the randomization code. All instances of unblinding will be recorded, and the reason for unblinding will be documented in the study records.
Procedures
The planned procedures were included in Table 1. Briefly, patients will undergo a comprehensive screening including medical history, physical examination, vital signs, laboratory tests (hematology, biochemistry, coagulation, urinalysis), electrocardiography (ECG), BRCA1/2 and HRD status assessment, imaging (CT/MRI), and CA-125 level measurement. During the treatment phase, procedures will include administration of chemotherapy and bevacizumab, monitoring of hypersensitivity, repeated imaging assessments per RECIST 1.1, safety laboratory tests, and evaluation of quality of life using EORTC questionnaires. Maintenance treatment includes administration of olaparib for eligible patients and continuous monitoring of adverse events. Follow-up visits will assess survival and further anticancer treatment every 12 weeks until study completion or patient death.
Eligibility criteria
Inclusion criteria
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1.
Age ≥ 18 years;
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2.
Obtaining the conscious and voluntary consent of the patient to participate in the study.
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3.
The ability and readiness to comply with the requirements of the research protocol;
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4.
Stage III-IV (according to FIGO) high-grade ovarian cancer (G2 or G3) or primary peritoneal cancer;
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5.
Assessed the presence of pathogenic mutations in BRCA1/2 and known HRD status;
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6.
Previous disqualification from the PDS and qualification for neoadjuvant chemotherapy due to ovarian cancer;
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7.
ECOG score 0–1;
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8.
Results of blood morphology examination: (a) PLT ≥ 1.5 × 105/mm3; (b) LEU ≥ 3.0 × 109/L; (c) NEU ≥ 1.5 × 109/L; (d) HGB ≥ 10.0 g/dL;
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9.
Coagulation markers: (e) APTT ≤ 1.5 × upper limit of normal (ULN); (f) PT/INR ≤ 1.5 × ULN
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10.
Liver and kidney function: (g) total bilirubin ≤ 1.5 × ULN (excluding patients with Gilbert’s syndrome); (h) AST and ALAT ≤ 2.5 × ULN (5 × ULN in patients with liver metastases); (i) creatinine ≤ 1.5 × ULN;
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11.
Systolic BP < 140 mmHg and/or diastolic BP ≤ 90 mmHg;
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12.
The postmenopausal period or exclusion of pregnancy in reproductive-aged women prior to administration of the first dose of the investigational drug.
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13.
There are no contraindications for the use of bevacizumab, carboplatin, or paclitaxel according to the Summary of Product Characteristics;
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14.
There are no contraindications for the use of olaparib according to the Summary of Product Characteristics (applies to patients with BRCA1/2 mutations and/or HRD positive).
Additional inclusion criteria:
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1.
A complete or partial response to neoadjuvant chemotherapy;
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2.
Undergoing delayed debulking surgery after neoadjuvant chemotherapy, regardless of the presence and extent of residual disease;
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3.
Three cycles of neoadjuvant chemotherapy based on platinum and paclitaxel with bevacizumab at a dose of 7.5 mg/kg b.w. were administered;
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4.
Interval debulking surgery performed within 8 weeks before inclusion in the study;
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5.
Availability of a paraffin block with a formalin-fixed primary tumor sample (FFPE);
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6.
For those capable of reproduction, it is necessary to either abstain from heterosexual sexual intercourse or utilize two reliable means of contraception. This commitment should begin 4 weeks before the initiation of the study, continue throughout the therapy period, during any gaps in dosage, and for 3 months following the completion of the drug regimen.
Exclusion criteria
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1.
Malignant tumors have occurred synchronously or been treated within the last 3 years. This does not apply to low metastatic potential tumors such as in situ tumors: breast, cervix, and skin;
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2.
An adverse event associated with neoadjuvant therapy of grade ≥ 3, according to the CTCAE v.5.0 classification, not resolved or decreased to grade 1 before randomization;
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3.
Clinically significant medical history of cardiovascular disease, including the following:
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a.
Hypertensive disease or hypertensive encephalopathy, defined according to the ESH 2023 guidelines [16];
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b.
Recent acute coronary syndrome ≤ 6 months from randomization, in accordance with the 2023 ESC guidelines [17];
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c.
Severe congestive heart failure (CHF) of Grade ≥ 3 according to the New York Heart Association (NYHA) classification [18];
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d.
Poorly controlled cardiac arrhythmia despite treatment (patients with well-controlled, persistent atrial fibrillation are eligible) or any clinically significant abnormalities in resting ECG (including QTc interval prolongation > 450 ms) as assessed by the investigator;
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e.
Peripheral vascular disease of grade > 3, according to the Rutherford classification [19];
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f.
A cerebrovascular incident, transient ischaemic attack, or subarachnoid haemorrhage experienced within 6 months before randomization;
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g.
History or evidence of existing hemorrhagic disorders within 6 months before randomization;
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h.
The presence of evidence of severe hemorrhage or significant coagulopathy, as determined by the investigator, precludes participation in the study;
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a.
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4.
History or clinical suspicion of brain metastases or spinal cord compression;
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5.
Central nervous system disease, unless effectively treated with regular medical therapy (e.g., uncontrolled seizures);
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6.
A significant injury or major surgical procedure within 4 weeks before randomization (excluding debulking surgery for ovarian, fallopian tube, or primary peritoneal cancer);
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7.
A healing wound, an active ulcer, or a bone fracture;
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8.
A history of abdominal fistula or gastrointestinal perforation associated with VEGF inhibitor therapy or active gastrointestinal bleeding within 6 months before the first investigated treatment;
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9.
Active peptic ulcer disease of the stomach or duodenum as assessed by the investigator;
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10.
Current clinically significant intestinal obstruction, including subocclusive disease, is associated with the underlying condition;
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11.
The inability to swallow the orally administered medication and the presence of gastrointestinal disorders that may interfere with the absorption of the tested medication.
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12.
Administration of anticoagulant or antiplatelet medications (excluding prophylactic dosing);
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13.
Known hypersensitivity reactions to bevacizumab, olaparib, carboplatin, paclitaxel, or any excipient;
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14.
Hypersensitivity to products derived from Chinese hamster ovary cells or other recombinant human or humanized antibodies;
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15.
Evidence of any other disease, metabolic dysfunction, or physical or laboratory test results that provide reasonable suspicion of a condition or state that contraindicates the use of the tested medication or exposes the patient to a high risk of treatment-related complications, as determined by the researcher;
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16.
Pregnancy or breastfeeding;
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17.
Patients who have previously participated in clinical trials may participate in this study if three times the half-life of the drug has passed between the time of the last administration of the study drug and the time of randomization;
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18.
The presence of a clinically known active, uncontrolled infection such as hepatitis B, hepatitis C, or HIV;
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19.
Any situation that, in the researcher’s opinion, may hinder the execution of the study according to the protocol or obtain written consent, such as alcohol abuse, drug abuse, other substance abuse, or addiction.
Interventions
Adjuvant treatment phase
Arm I and II: Three cycles of chemotherapy (paclitaxel 175 mg/m2 + carboplatin AUC 6.0) with bevacizumab 15 mg/kg administered every 21 days starting on the day of randomization (cycles 1–3).
Arm III and IV: Three cycles of chemotherapy (paclitaxel 175 mg/m2 + carboplatin AUC 6.0) with 7.5 mg/kg bevacizumab administered every 21 days starting on the day of randomization (cycles 1–3).
Patients without disease progression (confirmed via CT scan) will move to the maintenance treatment phase on the basis of their randomization results. This phase includes patients with a response to three postoperative chemotherapy cycles or stable disease who previously responded to neoadjuvant chemotherapy. Treatments will vary by arm, with the addition of olaparib for patients with BRCA1/2 mutations or confirmed HRD (see Fig. 1).
Maintenance treatment phase
Arm I: Olaparib 600 mg/day with bevacizumab 15 mg/kg every 21 days (cycles 4–19) for patients with BRCA1/2 mutations and/or HRD.
Arm II: Bevacizumab 15 mg/kg monotherapy every 21 days (cycles 4–19) for patients without BRCA1/2 mutations or HRD.
Arm III: Olaparib 600 mg/day with bevacizumab 7.5 mg/kg every 21 days (cycles 4–19) for patients with BRCA1/2 mutations and/or HRD.
Arm IV: Bevacizumab 7.5 mg/kg monotherapy every 21 days (Cycles 4–19) for patients without BRCA1/2 mutations or HRD.
After completing treatment, the participants entered the follow-up phase. During follow-up, patients will be monitored for overall survival, adverse events, and additional anticancer therapies at 9-week intervals.
The planned subgroup analysis will evaluate the influence of key biomarkers, such as the BRCA mutation status and HRD status, on treatment outcomes.
Outcomes
The primary objective of this study was to compare the efficacy of bevacizumab at doses of 7.5 mg/kg and 15 mg/kg in combination with adjuvant chemotherapy and as maintenance therapy with or without olaparib. This will be measured by the objective response rate (ORR), the percentage of patients who achieve either a complete or partial response to treatment, which will be assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) within 4 weeks after the conclusion of the adjuvant treatment phase. Additionally, progression-free survival (PFS) will be measured, defined as the time from randomization to disease progression/relapse (according to RECIST v.1.1) or death from any cause, whichever occurs first.
Efficacy secondary objectives will be measured by the ORR on the basis of the best overall response (BOR), which will be evaluated throughout the treatment period as per RECIST v.1.1. and time to start of first subsequent therapy or death (TFST), defined as the duration from initiating first-line chemotherapy to starting subsequent therapy or death.
Another secondary objective is the assessment of the safety profile and adverse event rates for both doses. We will measure the frequency and severity of adverse events (AEs), including serious adverse events (SAEs), classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.5.0). The frequency and severity of adverse events of special interest (AESIs) will be assessed according to the NCI CTCAE v.5.0. We will also evaluate the impact of treatment on quality of life via standardized quality-of-life questionnaires, specifically the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).
Data collection methods
Data collection in this clinical trial will follow a structured and multitiered approach to ensure accuracy, completeness, and compliance with regulatory standards. A custom-designed paper questionnaire will be utilized for continuous monitoring of quality of life and adverse events, allowing real-time documentation of any adverse effects related to the administered treatments. The research team reviewed the completeness of these records at each study visit to ensure data integrity. Additionally, all clinical data obtained during the trial will be systematically entered into an electronic case report form (eCRF) by designated research personnel. The eCRF system will comply with Good Clinical Practice (ICH GCP E6) and 21CFR Part 11 regulations and will feature an integrated interactive web response system (IWRS) to facilitate the randomization of patients into the study arms. Adverse events, including their severity, duration, and medical intervention, will be meticulously recorded in the eCRF. The principal investigator will be responsible for ensuring data accuracy and consistency between the eCRF and source documents, whereas a designated monitor will oversee the completeness and timeliness of data entry. In addition to the eCRFs, the study employs an electronic document management system to handle critical trial documentation. This will include the Electronic Investigator Site File (eISF) for research sites and the Electronic Trial Master File (eTMF) for the sponsor, both ensuring secure storage, accessibility, and regulatory compliance. The collection and monitoring of adverse events begin with the participant’s signing of the informed consent form and continue until the completion of treatment. Investigators will be responsible for reporting all adverse events to the sponsor, with detailed documentation of their characteristics and impact. Posttrial follow-up will be provided to ensure patient safety beyond study participation. Source documents, including original medical records, laboratory results, and study-related documentation, will be maintained in accordance with national and international regulations, ensuring proper traceability, accuracy, and completeness. Any modifications to source records must be justified for documented reasons, accompanied by signatures and dates. To ensure long-term data security and regulatory compliance, all clinical trial documentation will be archived securely for a minimum of 25 years or longer, as mandated by relevant legal frameworks or sponsor-specific requirements.
Statistical methods
The statistical analysis for this clinical trial was designed as a noninferiority study, with a focus on PFS as the primary endpoint. The null hypothesis assumes no significant difference in survival to progression among the study arms, whereas the alternative hypothesis suggests a potential 5% reduction in survival for specific treatment groups. The study aims to achieve 80% power at a 0.05 significance level, ensuring sufficient sensitivity to detect meaningful differences. A balanced allocation ratio of 1:1 between the study arms was established, with adjustments made for an anticipated 20% dropout rate. Sample size calculations, performed via dedicated statistical tools, revealed that 332 patients should be randomized and stratified into four treatment arms. The sample size was determined based on the assumption of equivalence in median PFS between bevacizumab doses of 7.5 mg/kg and 15 mg/kg, with an equivalence margin corresponding to a hazard ratio of 1.15. Using a one-sided α of 0.05 and 80% power, and assuming a median PFS of 18 months in the control arm, uniform patient accrual over 36 months, a minimum follow-up of 24 months, and a 5% drop-out rate, the required number of patients to be randomized was calculated as 332. PFS will be analysed via a Cox regression model, whereas the ORR will be assessed via log-linear analysis. Additionally, secondary endpoints, such as BOR, TFST, and quality of life measures, will be evaluated via logistic regression, Kaplan–Meier curves, Cox regression, and ANOVA methods. Safety assessments will include the analysis of AEs, categorized by frequency, severity, and potential association with the treatment, utilizing log-linear models and descriptive statistics. An interim analysis will be conducted when 50% of participants have been recruited, allowing for early study termination if substantial differences in response rates emerge. This comprehensive statistical approach ensures that both the efficacy and safety of the investigated treatment regimens are rigorously evaluated, providing a robust framework for assessing noninferiority and potential clinical benefits.