Clinical trial NCT05009082: Niraparib vs Niraparib Plus Bevacizumab in Patients With Platinum/Taxane-based Chemotherapy in Advanced Ovarian Cancer
Official title: Niraparib vs Niraparib in Combination With Bevacizumab in Patients With Carboplatinum-taxane Based Chemotherapy in Advanced Ovarian Cancer (A Multicentre Randomised Phase III Trial)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Ovarian Cancer
Fallopian Tube Cancer
Peritoneal Cancer
Keywords: High Grade Epithelial Ovarian Cancer
Advanced Ovarian Cancer
Niraparib
Bevacizumab
Carboplatin
Paclitaxel
Lead sponsor: AGO Study Group
Sponsor class: OTHER
Collaborators: name: European Network of Gynaecological Oncological Trial Groups (ENGOT)
First posted: 2021-08-17
Enrollment: 970
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Assessed frequently during the trial until observation of 586 PFS events or three years after Last Patient In, whichever occurs earlier
Secondary outcomes:
measure: PFS according to tumor BRCA status
timeFrame: Assessed frequently during the trial until observation of 586 PFS events or three years after Last Patient In, whichever occurs earlier
measure: Overall Survival (OS)
timeFrame: at every visit during the trial up to 66 months after Last Patient In
measure: Time to First Subsequent Therapy (TFST)
timeFrame: at every visit during the trial up to 66 months after Last Patient In
measure: Second Progression (PFS 2)
timeFrame: at every visit during the trial up to 66 months after Last Patient In
measure: Time to Second Subsequent Therapy (TSST)
timeFrame: at every visit during the trial up to 66 months after Last Patient In
measure: 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
timeFrame: at every visit during the trial up to safety follow up visit 30 days after last dose
measure: Effects on Quality of Life (QoL)
timeFrame: Assessed frequently during the trial up to 66 months after Last Patient In
Other outcomes:
Locations:
city: Amberg
country: Germany
facility: Klinikum St. Marien Amberg
city: Bad Homburg
country: Germany
facility: Hochtaunus-Kliniken
city: Bielefeld
country: Germany
facility: Onkologische Schwerpunktpraxis Bielefeld
city: Bottrop
country: Germany
facility: Onkologie Bottrop (OnkoDok GbR)
city: Brandenburg an der Havel
country: Germany
facility: Städt. Klinikum Brandenburg
city: Dortmund
country: Germany
facility: Klinikum Dortmund
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden
city: Düsseldorf
country: Germany
facility: Florence-Nightingale-Krankenhaus Düsseldorf
city: Düsseldorf
country: Germany
facility: Universitätsfrauenklinik Düsseldorf
city: Essen
country: Germany
facility: KEM Essen | Evang. Kliniken Essen-Mitte gGmbH
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt/Main
country: Germany
facility: Klinikum Frankfurt Höchst
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen
city: Gütersloh
country: Germany
facility: Klinikum Gütersloh
city: Halle
country: Germany
facility: Universitätsklinikum Halle
city: Hamburg
country: Germany
facility: Albertinen Krankenhaus
city: Hamburg
country: Germany
facility: Mammazentrum HH am Krankenhaus Jerusalem
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Gynäkologisch-Onkologische Praxis am Pelikanplatz
city: Heidelberg
country: Germany
facility: Universitätsklnikum Heidelberg
city: Heilbronn
country: Germany
facility: Klinikum am Gesundbrunnen / SLK-Kliniken Heilbronn GmbH
city: Hildesheim
country: Germany
facility: Gyn.-onkolog. Gemeinschaftspraxis Hildesheim
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
city: Karlsruhe
country: Germany
facility: ViDia Christliche Kliniken Karlsruhe
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kempten
country: Germany
facility: Klinikverbund Kempten-Oberallgäu gGmbH
city: Konstanz
country: Germany
facility: Klinikum Konstanz
city: Krefeld
country: Germany
facility: Zentrum für ambulante gynäkologische Onkologie am HELIOS Klinikum Krefeld
city: Köln
country: Germany
facility: St. Elisabeth-Krankenhaus Köln-Hohenlind
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Limburg
country: Germany
facility: St. Vincenz Krankenhaus
city: Ludwigsburg
country: Germany
facility: Klinikum Ludwigsburg
city: Luebeck
country: Germany
facility: UKSH Campus Lübeck
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim GmbH
city: Minden
country: Germany
facility: Mühlenkreiskliniken, Johannes Wesling Klinikum Minden
city: München
country: Germany
facility: LMU Klinikum München-Großhadern
city: München
country: Germany
facility: Rotkreuzklinikum München
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Neumarkt
country: Germany
facility: Klinikum Neumarkt
city: Nordhausen
country: Germany
facility: MVZ Nordhausen
city: Offenbach
country: Germany
facility: Klinikum Offenbach
city: Offenburg
country: Germany
facility: Ortenau Klinikum Offenburg-Kehl
city: Paderborn
country: Germany
facility: St. Vincenz Krankenhaus GmbH
city: Ravensburg
country: Germany
facility: Studienzentrum Onkologie Ravensburg
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brüder
city: Reutlingen
country: Germany
facility: Klinikum am Steinenberg
city: Rosenheim
country: Germany
facility: RoMed Klinikum Rosenheim
city: Rostock
country: Germany
facility: Klinikum Südstadt Rostock
city: Saalfeld
country: Germany
facility: Thüringen-Kliniken "Georgius Agricola"
city: Schweinfurt
country: Germany
facility: Leopoldina Krankenhaus Schweinfurt
city: Stralsund
country: Germany
facility: g.SUND
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart
city: Traunstein
country: Germany
facility: Klinikum Traunstein
city: Trier
country: Germany
facility: Klinikum Mutterhaus
city: Tuebingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinik Ulm
city: Wiesbaden
country: Germany
facility: St. Josefs-Hospital
city: Wolfsburg
country: Germany
facility: amO Wolfsburg
city: Worms
country: Germany
facility: Klinikum Worms
Study officials:
affiliation: KEM Essen | Evang. Kliniken Essen-Mitte gGmbH
name: Philipp Harter, MD, PhD
role: STUDY_CHAIR
References: