Niraparib With beVAcizumab After Complete cytoreductioN in Patients With ovArian Cancer

Ovarian Cancer Clinical Trial

— NIRVANA-1  

Official title:

Randomized Study of Paclitaxel-carboplatin Followed by Niraparib Compared to Paclitaxel-carboplatin-bevacizumab Followed by Niraparib+Bevacizumab in Patients With Advanced Ovarian Cancer, Following a Front-line Complete Surgery

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05183984
• Other study ID #: GINECO-OV129b
• Status: Recruiting
• Phase: Phase 2
• Start date: February 1, 2022
• Est. completion date: February 2030

Study information

• Verified date: January 2024
• Source: ARCAGY/ GINECO GROUP
• Contact: Sidonie Adam
• Phone: 1 84 85 20 18
• Email: sadam[@]arcagy.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Randomized, open label, phase II multicenter study to assess the efficacy niraparib versus niraparib +bevacizumab maintenance in patients with newly diagnosed stage IIIA/B/C high-grade epithelial ovarian cancer with no residual disease after frontline surgery and treatment by adjuvant platinum-basedchemotherapy +/-bevacizumab.

Description:

Phase II, randomized, open label, multicenterstudy. Randomization on a 1:1 ratio, stratification performed according to: BRCA status (local assessment) FIGO stage at diagnosis (IIIA versus IIIB/IIIC) Previous hyperthermic intraperitoneal chemotherapy (yes/no).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 390
• Est. completion date: February 2030
• Est. primary completion date: February 2027
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

For inclusion in the study, patient should fulfill the following criteria:

1. Female patient = 18 years of age.

2. Signed informed consent and ability to comply with treatment and follow-up.

3. Patient with newly diagnosed, a. Ovarian cancer, primary peritoneal cancer and/or fallopian-tube cancer, b. Histologically confirmed (based on local histopathological

findings):

• high grade serous or
• high grade endometrioid (grade 2 and 3) or
• other epithelial non mucinous and non-clear cell ovarian cancer in a patient with germline BRCA 1 or 2 deleterious mutation, c. At an advanced stage: FIGO stage IIIA to IIIC of the 2018 FIGO classification.

4. Patient having undergone frontline, complete cytoreductive surgery (i.e. no visible residual disease): The patient will be considered eligible once the ESGO Quality Assurance in Ovarian Cancer Surgery will have been filled out and validated

5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

6. Patient must have received one cycle of carboplatin AUC 5-6 + paclitaxel 175 mg/m²

7. Patient must have started cycle 1 chemotherapy no later than 6 weeks after surgery.

8. Patient must have a thorax-abdomen-pelvis CT scan between surgery and Cycle 1, with no evidence of disease.

9. Patient eligible for first line platinum-taxane chemotherapy:

10. Patient eligible for bevacizumab treatment in combination with chemotherapy and in maintenance. It must be started at the second chemotherapy cycle and be administered at a dose of 15mg/kg every 3 weeks up to a total of 15 months.

11. Patient must have normal organ and bone marrow function before first cycle of

chemotherapy:

• Hemoglobin = 9.0 g/dL.
• Absolute neutrophil count (ANC) = 1.5 x 109/L.
• Platelet count = 100 x 109/L.
• Total bilirubin = 1.5 x institutional upper limit of normal (ULN).
• Aspartate aminotransferase/Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) = 2.5 x ULN.
• Serum creatinine = 1. 5 x institutional ULN and GFR > 50 mL/min, by using an exact measure (ie. Iohexol clearance) or the most appropriate formula (Jeliffe, Cockroft Gault, MDRD, CKD-EPI) to the investigator's discretion.
• Patient not receiving anticoagulant medication who has an International Normalized Ratio (INR) =1.5 and an Activated ProThrombin Time (aPTT) =1.5 x 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 site medical standard). If the patient is on oral anticoagulants, dose has to be stable for at least two weeks at the time of randomization.

12. Urine dipstick for proteinuria < 2+. If urine dipstick is =2+, 24-hour proteinuria must be <1 g.

13. Normal blood pressure or adequately treated and controlled hypertension (systolic BP = 140 mmHg and/or diastolic BP = 90 mmHg).

14. Formalin fixed paraffin embedded (FFPE) tumor sample from the primary cancer must be available for local BRCA testing and if possible HRD testing (optional).

15. For countries where this will apply to: a subject will be eligible for randomization in this study only if either affiliated to, or a beneficiary of a social security category.

Exclusion Criteria:

• 1. Patient with clear cell adenocarcinoma or carcinosarcoma, non-epithelial origin of the ovarian tumor, the fallopian tube or the peritoneal tumor (i.e. germ cell tumors).

2. Ovarian tumor of low malignant potential (e.g. borderline tumor), or mucinous carcinoma.

3. Patient with a diagnosis, detection, or treatment of another type of cancer = 3 years prior to initiating protocol therapy (except basal or squamous cell carcinoma of the skin and cervical cancer in situ that has been definitively treated and synchronous grade 1 stage 1 endometrial cancer) Patient with history of primary triple negative breast cancer may be eligible provided she completed her definitive anticancer treatment more than 3 years ago and she remains breast cancer disease free prior to start of study treatment.

4. Patient with synchronous high grade serous or clear cell adenocarcinoma or carcinosarcoma of the endometrium is not eligible.

5. Patient with myelodysplastic syndrome/acute myeloid leukemia history. 6. Patient receiving radiotherapy within 6 weeks prior to study treatment. 7. Previous allogenic bone marrow transplant. 8. Any previous treatment with PARP inhibitor. 9. Administration of other simultaneous chemotherapy drugs - except during a HIPEC procedure with cisplatin at PDS, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted as are steroid antiemetics).

10. Current or recent (within 10 days prior to randomization) chronic use of aspirin > 325 mg/day.

11. Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.

12. Clinically significant (e.g. active) cardiovascular disease, including:

• Myocardial infarction or unstable angina within = 6 months of randomization,
• New York Heart Association (NYHA) = grade 2 congestive heart failure (CHF),
• Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG.
• Peripheral vascular disease grade = 3 (e.g. symptomatic and interfering with activities of daily living [ADL] requiring repair or revision).

13. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA), Sub- Arachnoids Hemorrhage (SAH) or Posterior Reversible Encephalopathy Syndrome (PRES).

14. History or evidence of hemorrhagic disorders. 15. Evidence of bleeding diathesis or significant coagulopathy (in the absence of coagulation).

16. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to randomization) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in case of suspected spinal cord compression.

17. History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).

18. Significant traumatic injury during 4 weeks prior to randomization. 19. Non-healing wound, active ulcer, or bone fracture. Patient with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection is eligible but require 3 weekly wound examinations.

20. History of VEGF therapy related abdominal fistula or gastrointestinal perforation or active gastrointestinal bleeding within 6 months prior to the first study treatment.

21. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.

22. Patient with evidence of abdominal free air not explained by paracentesis or recent surgical procedure.

23. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications.

24. Pregnant or lactating women. 25. Participation in another clinical study with any intravenous or oral investigational product is not allowed. However, participation in a surgical clinical study including Hyperthermic Chemotherapy (HIPEC) during the surgical procedure is allowed.

26. Patient unable to swallow orally administered medication and patient with gastrointestinal disorders likely to interfere with absorption of the study medication.

27. Patient with a known contraindication or uncontrolled hypersensitivity to the components of paclitaxel, carboplatin, niraparib, bevacizumab, or their excipients.

28. Immunocompromised patient, e.g., with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids or patient who is known to be serologically positive for human immunodeficiency virus (HIV).

29. Participant has a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Ovarian Cancer
• Ovarian Neoplasms

Intervention

Drug:
• Chemotherapy
Chemotherapy (carboplatin + paclitaxel) will be administred by intravenous infusion, AUC 5-6 q3w - 5 cycles during the treatment period
• Bevacizumab-Awwb
MVASI (bevacizumab biosimilar) will be administrated by intravenous infusion at the second chemotherapy cycle for 5 cycles. the administration will continue during maintenance phase. Total bevacizumab duration therapy is 15 months.
• Niraparib
niraparib will be administered orally once daily continuously after chemotherapy (+/- bevacizumab) cycles (maintenance treatment period). Total niraparib duration mainance treatment period is 2 years.

Locations

Country	Name	City	State
France	ICO Paul Papin	Angers
France	Sainte Catherine Institut du cancer Avignon-Provence	Avignon
France	CHRU Besançon - Hôpital Jean Minjoz	Besançon
France	Clinique Tivoli-Ducos	Bordeaux
France	Institut Bergonié	Bordeaux
France	Hôpital Morvan CHRU de Brest	Brest
France	HCL - Groupe Hospitalier Est	Bron
France	Centre François Baclesse	Caen
France	Centre Hospitalier de Cholet	Cholet
France	Centre Jean Perrin	Clermont-Ferrand
France	Centre Georges François Leclerc	Dijon
France	CHU de Dijon - Bourgogne	Dijon
France	Groupe Hospitalier Mutualiste de Grenoble - Institut Daniel Hollard	Grenoble
France	CHU Grenoble-Alpes - Site Nord (La Tronche)	La Tronche
France	Centre Oscar Lambret	Lille
France	CHU de Limoges - Hôpital Dupuytren	Limoges
France	Centre Léon Bérard	Lyon
France	HCL - Hôpital de la Croix Rousse	Lyon
France	Hôpital Privé Jean Mermoz	Lyon
France	Hôpital Nord Marseille	Marseille
France	Institut Paoli Calmettes	Marseille
France	Institut régional du cancer de Montpellier	Montpellier
France	Centre Azuréen de Cancérologie	Mougins
France	ORACLE - Centre d'Oncologie de Gentilly	Nancy
France	Hôpital Privé du Confluent	Nantes
France	Centre ONCOGARD - Institut de cancérologie du Gard	Nîmes
France	CHR Orléans	Orléans
France	Groupe Hospitalier Diaconesses - Croix Saint-Simon	Paris
France	Groupe Hospitalier Pitié Salpêtrière	Paris
France	Hôpital cochin	Paris
France	Hôpital Européen Georges Pompidou	Paris
France	Hôpital Tenon	Paris
France	Institut Mutualiste Montsouris	Paris
France	HCL - Centre Hospitalier Lyon Sud (Hospices Civils de Lyon)	Pierre-Bénite
France	Centre CARIO - HPCA	Plérin
France	CHU de Poitiers - Hôpital de la Milétrie	Poitiers
France	Institut Jean Godinot	Reims
France	Centre Eugène Marquis	Rennes
France	Centre Henri Becquerel	Rouen
France	ICO - Centre René Gauducheau	Saint-Herblain
France	CHU de Saint-Etienne - Pôle de Cancérologie	Saint-Priest-en-Jarez
France	ICANS - Institut de cancérologie Strasbourg Europe	Strasbourg
France	Institut Claudius Regaud	Toulouse
France	CHU Tours - Hôpital Bretonneau	Tours
France	Gustave Roussy	Villejuif
Japan	Saitama Medical University International Medical Center	Saitama

Sponsors (1)

Lead Sponsor	Collaborator
ARCAGY/ GINECO GROUP

Countries where clinical trial is conducted

France,  Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free survival (PFS) rate up to 24 months		Progression-Free Survival (PFS) is defined as time from randomization until objective tumor progression or death, whichever occurs first, assessed up to 24 months.
Secondary	PFS2		PFS2 is defined as time from randomization to objective tumor progression on next-line treatment or death from any cause, assessed up to 5 years.
Secondary	Number of Participants with abnormal physical examinations, abnormal vital signs and abnormal findings according to CTC-AE v5		Through treatment completion for all participants, an average of 28 months
Secondary	Time to First Subsequent Treatment		TFST is defined as the time from the date of randomization to date of the first subsequent anticancer therapy or death, assessed up to 5 years.
Secondary	Time to Second Subsequent Treatment		TSST is defined as the time from the date of randomization to the earlier of the date of second subsequent chemotherapy start date, or death date, assessed up to 5 years.
Secondary	Long-term Overall Survival in both arms		from time of signature of informed consent, throughout the study period, assessed up to 5 years
Secondary	Confirmation of the predictive value (overall chemo-sensitivity) of the KELIM.	Repeated CA-125 assay repeated through study completion	From study start until the end of the study, assessed up to 5 years