Niraparib vs Niraparib Plus Bevacizumab in Patients With Platinum/Taxane-based Chemotherapy in Advanced Ovarian Cancer

Ovarian Cancer Clinical Trial

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)

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
• 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
• 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).

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Fallopian Tube Cancer
• Fallopian Tube Neoplasms
• Ovarian Cancer
• Ovarian Neoplasms
• Peritoneal Cancer

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