Optimizing bevacizumab dosing in first-line ovarian cancer treatment: the PGOG-ov1 trial

Abstract

Abstract

The management of advanced ovarian cancer has significantly developed with the integration of bevacizumab into standard therapeutic regimens. While the efficacy of bevacizumab has been established in trials such as GOG218, ICON7, and PAOLA-1, there remains a gap in understanding the advantages of the 7.5 mg/kg dose over the 15 mg/kg regimen. This study addresses this gap by evaluating the efficacy, safety, and cost effectiveness of these two dosing strategies, considering the heterogeneity of patient profiles, including BRCA mutation status and homologous recombination deficiency (HRD). This multicenter, randomized clinical trial will recruit patients with newly diagnosed, advanced-stage (FIGO III/IV) ovarian, fallopian tube, or primary peritoneal cancer. Participants will undergo three cycles of neoadjuvant chemotherapy with bevacizumab, followed by interval debulking surgery and randomization into four treatment arms stratified by BRCA and HRD status. Patients will receive either 7.5 mg/kg or 15 mg/kg bevacizumab in combination with chemotherapy during the adjuvant treatment phase and continue with maintenance therapy for up to 64 weeks, with or without the addition of olaparib. The primary endpoint is progression-free survival. The secondary endpoints include the overall response rate, quality of life, and safety profile. Data analysis focuses on subgroup evaluation of the influence of BRCA and HRD status on treatment outcomes. This study is expected to provide critical insights into optimizing bevacizumab dosing, potentially enabling the inclusion of cost-effective and safer treatment protocols without compromising efficacy.

Trial registration

EUCT number: 2023–509659-15–00. Registered on 09.07.2024.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-025-09062-8.

Introduction

Ovarian cancer is the fifth most common cancer and the fourth leading cause of cancer-related death among women worldwide. Over 70% of ovarian cancers are diagnosed at stage III or IV according to the International Federation of Gynecology and Obstetrics (FIGO) classification. One of the main reasons for late diagnosis is the lack of specific symptoms in the early stages of the disease. Ovarian cancer is most commonly diagnosed in women aged 55–70 years. A significant risk factor for ovarian cancer is mutations in the tumor suppressor genes BRCA1 and BRCA2, which are present in approximately 30% of diagnosed cases [1].

Proteins encoded by BRCA1/2 are part of the poly (ADP‒ribose) polymerase (PARP) family, which is responsible for repairing double-strand DNA breaks and is involved in homologous recombination processes [2]. The status of homologous recombination deficiency (HRD), classified as positive (HRD-deficient), negative (HR-proficient, HRP), or undefined, is another significant prognostic factor linked to BRCA1/2 mutations. These mutations disrupt repair mechanisms and increase genetic instability in cells. BRCA1/2 mutations are most often associated with poorly differentiated high-grade tumors. Approximately 75% of newly diagnosed ovarian cancers are classified as high-grade. At diagnosis, metastases are typically present, and the 5-year survival rate is less than 30% [3, 4].

While primary debulking surgery (PDS) achieves the best outcomes when treatment sequences are initiated, complete cytoreduction is often not feasible due to disease progression. In such cases, neoadjuvant chemotherapy (NACT) is the appropriate strategy. Studies such as EORTC 55791 [5] and CHORUS [4] demonstrated that NACT is a suitable approach for highly advanced patients with a low likelihood of achieving complete cytoreduction through surgery alone. The first-line treatment for ovarian cancer consists of surgical treatment combined with systemic therapy. For advanced cancers, this includes platinum- and paclitaxel-based chemotherapy, antiangiogenic treatment with bevacizumab during chemotherapy and maintenance therapy, and the use of PARP inhibitors as maintenance therapy following an objective response to treatment [6]. The introduction of bevacizumab (studies GOG218 [7] and ICON7 [8]), followed by PARP inhibitors (studies SOLO1 [9], PAOLA1 [10], PRIMA [11], and PRIME [12]), has shaped the model for first-line ovarian cancer therapy [5].

In Poland, bevacizumab has been used in therapeutic programs for a strictly defined group of patients (stage IV, stage III with residual disease > 1 cm, and nonoperable cases) at a dose of 7.5 mg/kg body weight for 18 cycles (based on the ICON7 study). In other European countries, the GOG218 study model has been adopted, with a dose of 15 mg/kg body weight for 22 cycles. This model was applied in the PAOLA1 study [10], forming the basis for concurrent registration of bevacizumab and olaparib. The results demonstrated significant benefits for HRD-positive patients, including those with pathogenic BRCA1/2 mutations. Conversely, HRP patients did not benefit from adding olaparib to bevacizumab, and the drug is not currently registered for this group.

To date, no studies have directly compared the use of bevacizumab at doses of 7.5 mg/kg vs. 15 mg/kg in newly diagnosed ovarian cancer patients. Data from other cancers (e.g., lung cancer) suggest no differences in treatment efficacy but a significant reduction in adverse effects with the lower dose [13]. On the basis of clinical data and our experience, a dose of 7.5 mg/kg in high-risk patients after induction therapy following current standards will provide comparable efficacy with a better safety profile than 15 mg/kg. Additionally, we aimed to evaluate the efficacy of combining bevacizumab 15 mg/kg with olaparib (300 mg twice daily) vs. bevacizumab 7.5 mg/kg with olaparib in ovarian cancer patients.

Here, we present “A multicentre, four-arm, randomized, double-blind study assessing the dose equivalence of bevacizumab in first-line therapy for ovarian cancer (PGOG-ov1)” clinical trial protocol overview. We present the following hypotheses: (1) Bevacizumab at a dose of 7.5 mg/kg is equivalent to 15 mg/kg in combination with adjuvant chemotherapy in first-line treatment and as maintenance therapy with or without olaparib in advanced high-grade ovarian, fallopian tube, or primary peritoneal cancer; (2) when combined with adjuvant chemotherapy and/or olaparib, bevacizumab at 7.5 mg/kg has a better safety profile than 15 mg/kg; and (3) bevacizumab at 7.5 mg/kg improves quality of life compared with 15 mg/kg in the same therapeutic settings.

Study design

The study is planned to include 10 centers evenly distributed across Poland to ensure an appropriate patient cohort. All the participating centers collaborate under the Polish Gynecologic Oncology Group (a body of the Polish Society of Gynecologic Oncology) and have extensive experience conducting clinical trials for female genital tract cancers, including ovarian cancer.

The total treatment duration was 76 weeks, with a maximum participation time of 152 weeks for each patient. The screening (up to 4 weeks) begins once the patient provides informed consent. Eligible patients will include those with newly diagnosed, poorly differentiated ovarian, fallopian tube, or primary peritoneal cancer at FIGO stage III or IV who have undergone three cycles of neoadjuvant chemotherapy with bevacizumab at a dose of 7.5 mg/kg and interval debulking surgery. After completing the screening phase and confirming eligibility criteria, patients will be randomized at a 1:1:1:1 ratio to one of four arms, stratified by BRCA1/2 mutation status, HRD status, and the presence of residual disease. During this adjuvant treatment (12 weeks), patients will receive chemotherapy based on paclitaxel and carboplatin, continuing presurgical treatment, with varying doses of bevacizumab depending on the treatment arm (see Fig. 1). Maintenance therapy includes treatment with bevacizumab at a dose of 15 or 7.5 mg/kg of body weight. Patients with BRCA1/2 mutations or HRD-positive status receive olaparib as their additional maintenance treatment (60 weeks). After this time, the follow-up phase starts at 72 weeks (Figs. 1 and 2).

Fig. 1.

Project duration

Fig. 2.

The PGOG-ov1 trial design involved randomizing patients into four arms and outlining the treatment approaches and the follow-up phase. Adjuvant therapy includes chemotherapy based on carboplatin AUC6 along with paclitaxel at 175 mg/kg of body weight and bevacizumab at a dose of 15 or 7.5 mg/kg of body weight. Maintenance therapy includes treatment with bevacizumab at a dose of 15 or 7.5 mg/kg of body weight. Patients with BRCA1/2 mutations or HRD-positive status receive olaparib as their additional maintenance treatment. BEV, bevacizumab; b.w., body weight; HRD, homologous recombination deficiency

The total duration of patient treatment in the study was a maximum of 76 weeks (up to 19 months), and the patient’s total duration of participation in the study was a maximum of 152 weeks (up to 38 months).

Methods

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.

Table 1.

Schedule of study procedures and assessments across PGOG-ov1 study phases

a. Laboratory tests in C1D1 should only be performed if screening tests were performed more than 7 days before C1D1; B-HCG more than 3 days before C1D1

b. CT scans will be performed in the screening phase, after the end of adjuvant treatment and then at 12-week intervals (± 7 days) from the beginning of BEV (C4D1) regardless of possible shifts in treatment cycles. If the patient has a CT scan result that meets the protocol assumptions, performed within 4 weeks before enrollment in the study, it can be used and the CT scan in the screening phase can be omitted

¹All screening tests should be performed before randomization

²Cycle 1 of maintenance treatment will occur 3 weeks after the end of cycle 3 of adjuvant treatment. Bevacizumab will be administered every 3 weeks for 16 consecutive maintenance cycles or until disease progression (PD) or intolerable toxicity

³The End of Treatment (EOT) visit will occur 3 weeks after the last dose of study drug, regardless of the reason for discontinuation, unless the patient withdraws consent to participate in the study

⁴All patients will be followed up every 12 weeks until death or up to 72 weeks from the study EOT or until the end of the study, whichever comes first. Visits will be conducted by telephone

⁵All End of Study (EOS) visits will occur up to 72 weeks from the EOT or at the time of study end/discontinuation, unless the patient dies sooner

⁶Only for participants who consent to biobanking

⁷Patient age, gender, race, self-reported ethnicity

⁸Vital signs (including blood pressure, heart rate, and temperature) will be assessed prior to Bevacizumab administration and will be measured after 5 min of rest (in a sitting position)

⁹Height will be measured only at screening

¹⁰Laboratory tests will be performed on day 1 of each cycle. Laboratory samples will be analyzed in a local laboratory

¹¹A serum pregnancy test (β-HCG) should be performed only in patients who retained reproductive potential (FCBP) at the screening visit, within 3 days prior to day 1 of each study cycle and the EOT visit, or at any time if pregnancy is suspected. The β-HCG test will be analyzed in a local laboratory

¹²Paclitaxel and carboplatin will be administered on day 1 of each cycle during adjuvant treatment

¹³Applies only to arms I and III, patients with homologous recombination deficient status. Olaparib will be dispensed from C6D1 or C7D1 to C19D1

¹⁴Imaging tests will be performed within 4 weeks prior to the start of treatment in the study and then every 12 weeks regardless of treatment cycles or when progression is suspected according to RECIST 1.1

¹⁵Imaging of the head will be performed only in clinically justified cases, including suspected brain metastases or other CNS lesions. CT/MRI of the brain is mandatory (within 4 weeks before randomization) in the case of suspected brain metastases. MRI of the spine will be performed only in clinically justified cases (within 4 weeks before randomization), including suspected spinal cord compression

¹⁶Assessment of response to treatment will be based on the CA-125 marker. In the case of suspected progression, an imaging test (CT or MRI) should be performed within 14 days

¹⁷QLQ-C30 and QLQ-OV28 EORTC quality of life questionnaires, completed by the patient

¹⁸All medications used during the study, as well as all medications taken within 30 days of day 1 of cycle 1 during adjuvant therapy and up to 28 days after the last dose of study drug, until the EOT visit

¹⁹Adverse events will be assessed from the date of informed consent until 28 days after the last dose of study drug, regardless of the relationship to the study drug. If an adverse drug reaction (ADR) is ongoing at the EOT visit, ADR monitoring will continue until one of the following occurs: resolution or improvement from baseline, reassessment of the relationship as unrelated to the study drug, initiation of new anticancer therapy, confirmation from the investigator that no further improvement can be achieved before the expected end of clinical or safety data collection, or final database closure. For patients who do not participate in the follow-up phase, the last assessed AE status will be collected

²⁰To be performed when clinically indicated. PCR, ELISA, and cassette tests are acceptable

²¹Applies to patients who become pregnant during the study

BEV bevacizumab, ECOG Eastern Cooperative Oncology Group, HR heart rate, SBP systolic blood pressure, DBP diastolic blood pressure, ECG electrocardiography, EOS End of Study, EOT End of Treatment, MRI magnetic resonance imaging, CT computed tomography

Eligibility criteria

Inclusion criteria

1. Age ≥ 18 years;

2. Obtaining the conscious and voluntary consent of the patient to participate in the study.

3. The ability and readiness to comply with the requirements of the research protocol;

4. Stage III-IV (according to FIGO) high-grade ovarian cancer (G2 or G3) or primary peritoneal cancer;

5. Assessed the presence of pathogenic mutations in BRCA1/2 and known HRD status;

6. Previous disqualification from the PDS and qualification for neoadjuvant chemotherapy due to ovarian cancer;

7. ECOG score 0–1;

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;

9. Coagulation markers: (e) APTT ≤ 1.5 × upper limit of normal (ULN); (f) PT/INR ≤ 1.5 × ULN

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;

11. Systolic BP < 140 mmHg and/or diastolic BP ≤ 90 mmHg;

12. The postmenopausal period or exclusion of pregnancy in reproductive-aged women prior to administration of the first dose of the investigational drug.

13. There are no contraindications for the use of bevacizumab, carboplatin, or paclitaxel according to the Summary of Product Characteristics;

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:

1. A complete or partial response to neoadjuvant chemotherapy;

2. Undergoing delayed debulking surgery after neoadjuvant chemotherapy, regardless of the presence and extent of residual disease;

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;

4. Interval debulking surgery performed within 8 weeks before inclusion in the study;

5. Availability of a paraffin block with a formalin-fixed primary tumor sample (FFPE);

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

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;

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;

3. Clinically significant medical history of cardiovascular disease, including the following:

   1. Hypertensive disease or hypertensive encephalopathy, defined according to the ESH 2023 guidelines [16];
   2. Recent acute coronary syndrome ≤ 6 months from randomization, in accordance with the 2023 ESC guidelines [17];
   3. Severe congestive heart failure (CHF) of Grade ≥ 3 according to the New York Heart Association (NYHA) classification [18];
   4. 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;
   5. Peripheral vascular disease of grade > 3, according to the Rutherford classification [19];
   6. A cerebrovascular incident, transient ischaemic attack, or subarachnoid haemorrhage experienced within 6 months before randomization;
   7. History or evidence of existing hemorrhagic disorders within 6 months before randomization;
   8. The presence of evidence of severe hemorrhage or significant coagulopathy, as determined by the investigator, precludes participation in the study;

4. History or clinical suspicion of brain metastases or spinal cord compression;

5. Central nervous system disease, unless effectively treated with regular medical therapy (e.g., uncontrolled seizures);

6. A significant injury or major surgical procedure within 4 weeks before randomization (excluding debulking surgery for ovarian, fallopian tube, or primary peritoneal cancer);

7. A healing wound, an active ulcer, or a bone fracture;

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;

9. Active peptic ulcer disease of the stomach or duodenum as assessed by the investigator;

10. Current clinically significant intestinal obstruction, including subocclusive disease, is associated with the underlying condition;

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.

12. Administration of anticoagulant or antiplatelet medications (excluding prophylactic dosing);

13. Known hypersensitivity reactions to bevacizumab, olaparib, carboplatin, paclitaxel, or any excipient;

14. Hypersensitivity to products derived from Chinese hamster ovary cells or other recombinant human or humanized antibodies;

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;

16. Pregnancy or breastfeeding;

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;

18. The presence of a clinically known active, uncontrolled infection such as hepatitis B, hepatitis C, or HIV;

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.

Discussion

Ovarian cancer remains a significant therapeutic challenge, particularly in advanced stages (FIGO III/IV), where relapse rates are high despite standard treatment. Bevacizumab, an antiangiogenic monoclonal antibody, has become a fundamental therapy for ovarian cancer, as demonstrated in pivotal trials, such as those involving GOG218 [7], ICON7 [8], and PAOLA1 [10]. However, while these studies established the efficacy of bevacizumab in combination with chemotherapy and as maintenance therapy, they primarily utilized the 15 mg/kg bw dose.

The current study addresses an important clinical question: can a lower 7.5 mg/kg bw dose provide comparable efficacy to a higher dose in specific patient subgroups, such as those with BRCA mutations or HRD-positive tumors? This is a crucial consideration given the potential for reduced toxicity, lower treatment costs, and broader accessibility without compromising patient outcomes.

The GOG218 trial established the benefit of bevacizumab in prolonging PFS in advanced ovarian cancer patients when bevacizumab was combined with chemotherapy and maintenance therapy [7]. The study utilized a 15 mg/kg dose without exploring lower doses, leaving a gap in understanding dose-dependent efficacy. The ICON7 trial demonstrated that a 7.5 mg/kg dose of bevacizumab improved PFS, particularly in high-risk subgroups [8]. However, the study did not directly compare the 7.5 mg/kg dose to the 15 mg/kg dose, and the shorter duration of bevacizumab maintenance therapy limited its conclusions. The PAOLA1 trial highlighted the synergy between bevacizumab and olaparib in HRD-positive patients but exclusively used a 15 mg/kg dose of bevacizumab, precluding conclusions about alternative dosing regimens [10]. Nevertheless, robust, direct evidence comparing the efficacy and safety of 7.5 mg/kg vs. 15 mg/kg bevacizumab in ovarian cancer, particularly in combination with olaparib or in biomarker-selected populations, is limited. This study aims to fill this gap by evaluating both stratified doses and addressing the critical question of dose optimization for clinical efficacy and cost-effectiveness.

The results of this study have the potential to shape clinical practice globally by providing evidence on the efficacy and tolerability of different bevacizumab dosing regimens in combination with olaparib and standard chemotherapy. The results may support the use of lower-dose bevacizumab regimens without compromising efficacy or expanding accessibility, which may provide a basis for further research into optimizing bevacizumab use across different cancer types, particularly in regions with differing standards of care. Moreover, the cost of bevacizumab at the 15 mg/kg dose substantially burdens healthcare systems. A shift to the 7.5 mg/kg dose could significantly reduce costs, making this effective therapy more accessible in resource-constrained settings such as Poland and other middle-income countries. Low-dosing regimens could improve availability in regions with limited healthcare funding, broadening the global impact of antiangiogenic therapy in ovarian cancer patients.

This study has several limitations. With a 152-week maximum participation time, there is a risk of patient discontinuation due to withdrawal, loss to follow-up, or death, which could impact the robustness of long-term outcomes such as overall survival. Moreover, the interplay between BRCA mutations, HRD status, and treatment response is complex, and these factors may obscure the comparative effects of the two bevacizumab doses unless adequately stratified and analyzed. The results may not be fully generalizable to healthcare systems with different clinical practices, reimbursement policies, or patient demographics.

This study has the potential to significantly impact clinical practice by optimizing bevacizumab dosing, improving patient outcomes, and addressing economic challenges in cancer treatment, ultimately contributing to more sustainable and patient-centered healthcare systems.

Trial status

Protocol version 2.2, 01/07/2024.

Enrollment has not yet started in the participating centers. Competition of recruitment is estimated to be in December 2026.

Name and contact information for the trial sponsor: Medical University of Lublin, 1 Raclavice Alee, 20–059 Lublin, Poland;

Authors’ contributions

All authors of the manuscript are co-authors of the PGOG-ov1 trial protocol. All the authors contributed equally to the intellectual development of this manuscript. All the authors performed the drafting and preliminary research needed to formulate this protocol. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding

Medical Research Agency, Poland (Project number 2023/ABM/01/00015–00).

Data Availability

The data supporting the results of this study are not yet publicly available due to their sensitivity and are available from the study sponsor through the corresponding author upon reasonable request. The data are located in controlled-access storage in the sponsor's repository, Medical University of Lublin.

Declarations

Ethics approval and consent to participate

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 by investigators from all subjects when patients are enrolled in the study.

Competing interests

Marta Ostrowska-Lesko: Clinical trials: CELLTRION INC. Stocks and shares: M2 Innovations, EBMed.

Marcin Bobinski: Clinical trials: Astra Zeneca, MSD, Aeterna Zentalis, Clovis, Corcept Therapeutics; Lectures and Grants: GSK, Astra Zeneca, Abbvie; Stocks and shares: M2 Innovations, Ryvu Therapeutics, PolTreg, ScopeFluidics.

Radoslaw Madry: Lecturer: Abbvie, Amgen; AstraZeneca; GSK; Roche; MSD; Medisson. Research for: Amgen, Antisoma, AstraZeneca, Bayer, GSK, Glycotope GmbH, Janssen, Menarini, Morphotek, MSD, OSI Pharmaceuticals, PharmaMar, Roche, Sanofi, Sotio, Tesaro. Consultancy for: AstraZeneca, GSK, MSD, Pharma@, Roche.

This study was not funded or supported by the above partners, and the author did not receive any financial benefits related to this research.