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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05009082
Other study ID # AGO-OVAR 28
Secondary ID 2021-001271-16EN
Status Recruiting
Phase Phase 3
First received
Last updated
Start date September 13, 2022
Est. completion date September 2030

Study information

Verified date April 2024
Source AGO Study Group
Contact Sandra Polleis
Phone +49 611 880467
Email spolleis@ago-ovar.de
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This is an international, multicenter, randomized, open, Phase III trial to evaluate the efficacy and safety of carboplatin/paclitaxel/bevacizumab followed by bevacizumab and niraparib compared to carboplatin/paclitaxel followed by niraparib in patients with newly diagnosed advanced ovarian cancer.


Description:

Eligible patients will be those patients with newly diagnosed, histologically confirmed, advanced (FIGO stage III/IV, except FIGO stage IIIA2 without nodal involvement) invasive high grade epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer, who have either undergone upfront primary surgery or plan to undergo chemotherapy with interval debulking surgery (IDS). In addition, patients should not have any medical contraindications that would exclude treatment with bevacizumab and/or niraparib. All eligible patients will receive the first cycle of chemotherapy (carboplatin area under curve [AUC] 5 and paclitaxel 175 mg/m²) as part of Study Run-In-Period (cycle 1). In parallel, central laboratory will determine the breast cancer (BRCA) status in tumor tissue (tBRCA). All patients with a valid central tBRCA test result will be randomized prior to day 1 of cycle 2 in a 1:1 ratio in the following treatment arms: Arm 1: Patients will receive further 5 cycles of carboplatin and paclitaxel q21d followed by niraparib once daily for up to a total of 3 years Arm 2: Patients will receive further 5 cycles of carboplatin and paclitaxel plus bevacizumab q21d followed by bevacizumab q21d (for up to 1 year) and niraparib once daily for up to a total of 3 years. The study aims to investigate, if the treatment strategy of carboplatin / paclitaxel / bevacizumab / niraparib is superior to the treatment of carboplatin / paclitaxel / niraparib-Inhibitor in an all-comer population.


Recruitment information / eligibility

Status Recruiting
Enrollment 970
Est. completion date September 2030
Est. primary completion date February 2028
Accepts healthy volunteers No
Gender Female
Age group 18 Years and older
Eligibility Inclusion Criteria: 1. Signed written informed consent obtained prior to initiation of any study-specific procedures and treatment as confirmation of the patient's awareness and willingness to comply with the study requirements. 2. Female patients = 18 years with histologically confirmed primary advanced invasive high grade epithelial ovarian cancer, peritoneal cancer, or fallopian tube cancer FIGO III/IV (except FIGO stage IIIA2 without nodal involvement) according to recent FIGO classification (= FIGO stage IIIB - IV according to FIGO 2009 classification). 3. All patients must have had either upfront primary debulking surgery OR plan to undergo chemotherapy with interval debulking surgery. 4. Patients must have available tumor samples to be sent to central laboratory as formalin-fixed, paraffin-embedded (FFPE) sample for determination of BRCA status prior to randomization for stratification. 5. Patients must be able to commence systemic therapy within 8 weeks of cytoreductive surgery. 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. 7. Estimated life expectancy > 3 months. 8. Adequate bone marrow function (within 28 days prior to day 1, cycle 1) - Absolute Neutrophil Count (ANC) = 1.5 x 10^9/L - Platelets (PLT) = 100 x 10^9/L - Hemoglobin (Hb) = 9 g/dL (can be post-transfusion) 9. Adequate coagulation parameters (within 28 days prior to day 1, cycle 1) - Patients not receiving anticoagulant medication who have an International Normalized Ratio (INR) = 1.5 and an Activated ProThrombin Time (aPTT) = 1.5 x institutional upper limit of normal (ULN). - The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to institution medical standard) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of day 1, cycle 1. 10. Adequate liver and kidney function (within 28 days prior to day 1, cycle 1) - Total bilirubin = 1.5 x ULN (= 2.0 x ULN in patients with known Gilbert's syndrome) OR direct bilirubin = 1.0 x ULN. - Aspartate aminotransferase / Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT) and Alanine aminotransferase / Serum Glutamic Pyruvate Transaminase (ALAT/SGPT) = 2.5 x ULN, unless liver metastases are present, in case of liver metastases values must be = 5 x ULN. - Urine dipstick for proteinuria < 2+. If urine dipstick is = 2+, 24 hour urine must demonstrate = 1 g of protein in 24 hours. - Serum creatinine = 1.5 x upper limit of normal (ULN) or calculated creatinine clearance = 30 mL/min using the Cockcroft-Gault equation. 11. Patients must have normal blood pressure (BP) or adequately treated and controlled BP, with a systolic BP of = 140 mmHg and diastolic BP of = 90 mmHg for eligibility. Patients must have a BP of = 140/90 mmHg taken in the clinic setting by a medical professional within 4 weeks prior to day 1, cycle 1. 12. Negative urine or serum pregnancy test within 7 days prior to day 1, cycle 1 in women of childbearing potential (WOCBP), confirmed prior to treatment on day 1. 13. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 6 months after administration of the last dose of medication. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries, fallopian tubes, and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include but are not limited to bilateral tubal ligation and/or occlusion, male sterilization, and intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. 14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, that include the completion of patient-reported outcomes questionnaires. Exclusion Criteria: 1. Non-epithelial tumor origin of the ovary. 2. Ovarian tumors of low malignant potential (e.g. borderline tumors) and low grade tumors. 3. Planned intraperitoneal cytotoxic chemotherapy. 4. Malignancies other than ovarian cancer within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%) and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, ductal carcinoma in situ of the breast, or stage I p53 wild type endometrial cancer). 5. Prior systemic treatment for ovarian cancer. 6. Prior treatment with Poly adenosine diphosphate ribose polymerase (PARP) inhibitor. 7. Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted). 8. Prior randomization in this trial. 9. Major surgery within 1 week of starting study treatment or patient who has not completely recovered from the effects of any major surgery. Core biopsy or other minor surgical procedure within 7 days prior to day 1, cycle 1 is permitted. 10. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to day 1, cycle 1) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to day 1, cycle 1) in case of suspected spinal cord compression. 11. Significant traumatic injury during 4 weeks preceding the potential first dose of bevacizumab. 12. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to day 1, cycle 1. 13. History or evidence of thrombotic or hemorrhagic disorders within 3 months prior to day 1, cycle 1. 14. History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy e.g. uncontrolled seizures. 15. Pregnant or lactating women. 16. Treatment with any other investigational agent, or participation in another clinical trial testing a drug within 4 weeks or 5 times the half-life of the drug, whichever is longer, prior to day 1, cycle 1 or concomitantly with this trial. 17. Known hypersensitivity to bevacizumab and its excipients, Chinese hamster ovary cell products or other recombinant human or humanized antibodies. Known hypersensitivity to niraparib, paclitaxel and carboplatin and its components or excipients. 18. Non-healing wound, active ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require 3-weekly wound examinations. 19. Clinically significant cardiovascular disease, including - Myocardial infarction or unstable angina within 6 months of day 1, cycle 1 - New York Heart Association (NYHA) Grade 2 Congestive Heart Failure (CHF), - Poorly controlled cardiac arrhythmia despite medication (patients with rate-controlled atrial fibrillation are eligible) - Grade = 3 peripheral vascular disease (i.e. symptomatic and interfering with activity of daily living (ADL) requiring repair or revision) - Significant vascular disease including aortic aneurysm requiring surgical repair 20. Pre-existing sensory or motor neuropathy = Grade 2. 21. Any prior history of hypertensive crisis (CTCAE grade 4) or hypertensive encephalopathy. 22. Patients with a history of or current Nephrotic syndrome. 23. Bowel obstruction (including subocclusive disease). 24. History of abdominal fistula or tracheoesophageal fistula or gastrointestinal perforation or active gastrointestinal bleeding or anastomotic insufficiency within 6 months of day 1, cycle 1. 25. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of niraparib. 26. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications. 27. Any known history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). 28. Previous allogeneic bone marrow transplant or previous solid organ transplantation. 29. Current or recent (within 10 days prior to day 1, cycle 1) chronic use of aspirin > 325 mg/day. Patients treated with other inhibitors of platelet aggregation such as clopidogrel, prasugrel, ticlopidine, tirofibane or dipyridamole should not be included into the trial. 30. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. This includes also any psychiatric disorder that prohibits obtaining informed consent. 31. Patient has known active hepatitis B or hepatitis C. 32. Patient has a history of Posterior Reversible Encephalopathy Syndrome (PRES).

Study Design


Intervention

Drug:
Carboplatin
Area under curve (AUC) 5, intravenous, on day 1 every 3 weeks for 6 cycles
Paclitaxel
175 mg/m², intravenous, on day 1 every 3 weeks for 6 cycles
Bevacizumab
7.5 mg/kg or 15 mg/kg (according to local standard), intravenous, on day 1 every 3 weeks starting from cycle 2 in combination with chemotherapy and thereafter for up to 1 year
Niraparib
200 or 300 mg capsules once daily for up to a total of 3 years

Locations

Country Name City State
Germany Klinikum St. Marien Amberg Amberg
Germany Hochtaunus-Kliniken Bad Homburg
Germany Onkologische Schwerpunktpraxis Bielefeld Bielefeld
Germany Onkologie Bottrop (OnkoDok GbR) Bottrop
Germany Städt. Klinikum Brandenburg Brandenburg an der Havel
Germany Klinikum Dortmund Dortmund
Germany Universitätsklinikum Carl Gustav Carus Dresden Dresden
Germany Florence-Nightingale-Krankenhaus Düsseldorf Düsseldorf
Germany Universitätsfrauenklinik Düsseldorf Düsseldorf
Germany KEM Essen | Evang. Kliniken Essen-Mitte gGmbH Essen
Germany Universitätsklinikum Essen Essen
Germany Klinikum Frankfurt Höchst Frankfurt/Main
Germany Universitätsklinikum Gießen Gießen
Germany Klinikum Gütersloh Gütersloh
Germany Universitätsklinikum Halle Halle
Germany Albertinen Krankenhaus Hamburg
Germany Mammazentrum HH am Krankenhaus Jerusalem Hamburg
Germany Universitätsklinikum Hamburg-Eppendorf Hamburg
Germany Gynäkologisch-Onkologische Praxis am Pelikanplatz Hannover
Germany Universitätsklnikum Heidelberg Heidelberg
Germany Klinikum am Gesundbrunnen / SLK-Kliniken Heilbronn GmbH Heilbronn
Germany Gyn.-onkolog. Gemeinschaftspraxis Hildesheim Hildesheim
Germany Städtisches Klinikum Karlsruhe Karlsruhe
Germany ViDia Christliche Kliniken Karlsruhe Karlsruhe
Germany Klinikum Kassel Kassel
Germany Klinikverbund Kempten-Oberallgäu gGmbH Kempten
Germany St. Elisabeth-Krankenhaus Köln-Hohenlind Köln
Germany Klinikum Konstanz Konstanz
Germany Zentrum für ambulante gynäkologische Onkologie am HELIOS Klinikum Krefeld Krefeld
Germany Universitätsklinikum Leipzig Leipzig
Germany St. Vincenz Krankenhaus Limburg
Germany Klinikum Ludwigsburg Ludwigsburg
Germany UKSH Campus Lübeck Luebeck
Germany Universitätsmedizin Mainz Mainz
Germany Universitätsklinikum Mannheim GmbH Mannheim
Germany Mühlenkreiskliniken, Johannes Wesling Klinikum Minden Minden
Germany LMU Klinikum München-Großhadern München
Germany Rotkreuzklinikum München München
Germany Universitätsklinikum Münster Münster
Germany Klinikum Neumarkt Neumarkt
Germany MVZ Nordhausen Nordhausen
Germany Klinikum Offenbach Offenbach
Germany Ortenau Klinikum Offenburg-Kehl Offenburg
Germany St. Vincenz Krankenhaus GmbH Paderborn
Germany Studienzentrum Onkologie Ravensburg Ravensburg
Germany Krankenhaus Barmherzige Brüder Regensburg
Germany Klinikum am Steinenberg Reutlingen
Germany RoMed Klinikum Rosenheim Rosenheim
Germany Klinikum Südstadt Rostock Rostock
Germany Thüringen-Kliniken "Georgius Agricola" Saalfeld
Germany Leopoldina Krankenhaus Schweinfurt Schweinfurt
Germany g.SUND Stralsund
Germany Klinikum Stuttgart Stuttgart
Germany Klinikum Traunstein Traunstein
Germany Klinikum Mutterhaus Trier
Germany Universitätsklinikum Tübingen Tuebingen
Germany Universitätsklinik Ulm Ulm
Germany St. Josefs-Hospital Wiesbaden
Germany amO Wolfsburg Wolfsburg
Germany Klinikum Worms Worms

Sponsors (2)

Lead Sponsor Collaborator
AGO Study Group European Network of Gynaecological Oncological Trial Groups (ENGOT)

Country where clinical trial is conducted

Germany, 

Outcome

Type Measure Description Time frame Safety issue
Primary Progression Free Survival (PFS) Defined as the time from randomization to first progressive disease (PD) or death, whichever occurs earlier. PD is based on investigators assessment using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Assessed frequently during the trial until observation of 586 PFS events or three years after Last Patient In, whichever occurs earlier
Secondary PFS according to tumor BRCA status Defined as the time from randomization to first progressive disease (PD) or death, whichever occurs earlier. PD is based on investigators assessment using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Assessed frequently during the trial until observation of 586 PFS events or three years after Last Patient In, whichever occurs earlier
Secondary Overall Survival (OS) Defined as the time from randomization to death at every visit during the trial up to 66 months after Last Patient In
Secondary Time to First Subsequent Therapy (TFST) Defined as the time from randomization to the first subsequent treatment or death, whichever occurs earlier at every visit during the trial up to 66 months after Last Patient In
Secondary Second Progression (PFS 2) Defined as the time from randomization to the second progression or death, whichever occurs earlier at every visit during the trial up to 66 months after Last Patient In
Secondary Time to Second Subsequent Therapy (TSST) Defined as the time from randomization to the second subsequent treatment death whichever occurs earlier at every visit during the trial up to 66 months after Last Patient In
Secondary Number of participants with treatment-related adverse events (AE) and/or serious adverse events (SAEs) and/or AEs that led to premature withdrawal of trial treatment and/or interruptions/dose modifications Graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 at every visit during the trial up to safety follow up visit 30 days after last dose
Secondary Effects on Quality of Life (QoL) Questionnaires to be completed by patients and collected frequently during the trial Assessed frequently during the trial up to 66 months after Last Patient In
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