NIRVANA-1: Niraparib With beVAcizumab After Complete cytoreductioN in Patients With ovArian Cancer

Sponsor

ARCAGY/ GINECO GROUP (Other)

Overall Status

Recruiting

CT.gov ID

NCT05183984

Collaborator

(none)

390

Enrollment

Locations

Arms

Anticipated Duration (Months)

9.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer	Drug: Chemotherapy Drug: Bevacizumab-Awwb Drug: Niraparib	Phase 2

Detailed 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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

390 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Feb 1, 2022

Anticipated Primary Completion Date :

Jan 1, 2024

Anticipated Study Completion Date :

Jan 1, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ARM A: carboplatin/paclitaxel + niraparib carboplatin AUC 5-6 + paclitaxel 175 mg/m² q3w, 5 cycles, followed by niraparib 200* or 300 mg/d for 2 years.	Drug: Chemotherapy Chemotherapy (carboplatin + paclitaxel) will be administred by intravenous infusion, AUC 5-6 q3w - 5 cycles during the treatment period Drug: 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.
Experimental: ARM B: carboplatin/paclitaxel/bevaziumab + niraparib/bevacizumab carboplatin AUC 5-6 + paclitaxel 175 mg/m² + bevacizumab 15 mg/kg q3w, 5 cycles, followed by bevacizumab 15 mg/kg q3w for 15 months + niraparib 200*or 300 mg/d for 2 years.	Drug: Chemotherapy Chemotherapy (carboplatin + paclitaxel) will be administred by intravenous infusion, AUC 5-6 q3w - 5 cycles during the treatment period Drug: 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. Drug: 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.

Arm

Intervention/Treatment

Experimental: ARM A: carboplatin/paclitaxel + niraparib

carboplatin AUC 5-6 + paclitaxel 175 mg/m² q3w, 5 cycles, followed by niraparib 200* or 300 mg/d for 2 years.

Drug: Chemotherapy

Chemotherapy (carboplatin + paclitaxel) will be administred by intravenous infusion, AUC 5-6 q3w - 5 cycles during the treatment period

Drug: 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.

Experimental: ARM B: carboplatin/paclitaxel/bevaziumab + niraparib/bevacizumab

carboplatin AUC 5-6 + paclitaxel 175 mg/m² + bevacizumab 15 mg/kg q3w, 5 cycles, followed by bevacizumab 15 mg/kg q3w for 15 months + niraparib 200*or 300 mg/d for 2 years.

Drug: Chemotherapy

Chemotherapy (carboplatin + paclitaxel) will be administred by intravenous infusion, AUC 5-6 q3w - 5 cycles during the treatment period

Drug: 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.

Drug: Niraparib

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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.]
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]
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.]
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.]
Long-term Overall Survival in both arms [from time of signature of informed consent, throughout the study period, assessed up to 5 years]
Confirmation of the predictive value (overall chemo-sensitivity) of the KELIM. [From study start until the end of the study, assessed up to 5 years]
Repeated CA-125 assay repeated through study completion

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Female patient ≥ 18 years of age.
Signed informed consent and ability to comply with treatment and follow-up.
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.

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
Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
Patient must have received one cycle of carboplatin AUC 5-6 + paclitaxel 175 mg/m²
Patient must have started cycle 1 chemotherapy no later than 6 weeks after surgery.
Patient must have a thorax-abdomen-pelvis CT scan between surgery and Cycle 1, with no evidence of disease.
Patient eligible for first line platinum-taxane chemotherapy:
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.
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.

Urine dipstick for proteinuria < 2+. If urine dipstick is ≥2+, 24-hour proteinuria must be <1 g.
Normal blood pressure or adequately treated and controlled hypertension (systolic BP ≤ 140 mmHg and/or diastolic BP ≤ 90 mmHg).
Formalin fixed paraffin embedded (FFPE) tumor sample from the primary cancer must be available for local BRCA testing and if possible HRD testing (optional).
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).

Ovarian tumor of low malignant potential (e.g. borderline tumor), or mucinous carcinoma.
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.
Patient with synchronous high grade serous or clear cell adenocarcinoma or carcinosarcoma of the endometrium is not eligible.
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).
Current or recent (within 10 days prior to randomization) chronic use of aspirin > 325 mg/day.
Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.
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).

Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA), Sub- Arachnoids Hemorrhage (SAH) or Posterior Reversible Encephalopathy Syndrome (PRES).
History or evidence of hemorrhagic disorders. 15. Evidence of bleeding diathesis or significant coagulopathy (in the absence of coagulation).
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.
History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
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.
History of VEGF therapy related abdominal fistula or gastrointestinal perforation or active gastrointestinal bleeding within 6 months prior to the first study treatment.
Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.
Patient with evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
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.
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.
Patient unable to swallow orally administered medication and patient with gastrointestinal disorders likely to interfere with absorption of the study medication.
Patient with a known contraindication or uncontrolled hypersensitivity to the components of paclitaxel, carboplatin, niraparib, bevacizumab, or their excipients.
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).
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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	ICO Paul Papin	Angers	France	49055
2	Sainte Catherine Institut du cancer Avignon-Provence	Avignon	France	84918
3	CHRU Besançon - Hôpital Jean Minjoz	Besançon	France	25000
4	Clinique Tivoli-Ducos	Bordeaux	France	33000
5	Institut Bergonié	Bordeaux	France	33076
6	Hôpital Morvan CHRU de Brest	Brest	France	29200
7	HCL - Groupe Hospitalier Est	Bron	France
8	Centre François Baclesse	Caen	France	14076
9	Centre Hospitalier de Cholet	Cholet	France	49300
10	Centre Jean Perrin	Clermont-Ferrand	France	63011
11	CHU de Dijon - Bourgogne	Dijon	France	21000
12	Centre Georges François Leclerc	Dijon	France	21079
13	Groupe Hospitalier Mutualiste de Grenoble - Institut Daniel Hollard	Grenoble	France	38028
14	CHU Grenoble-Alpes - Site Nord (La Tronche)	La Tronche	France	38700
15	Centre Oscar Lambret	Lille	France	59020
16	CHU de Limoges - Hôpital Dupuytren	Limoges	France	87042
17	Centre Léon Bérard	Lyon	France	69373
18	Hôpital Privé Jean Mermoz	Lyon	France	69373
19	HCL - Hôpital de la Croix Rousse	Lyon	France
20	Institut Paoli Calmettes	Marseille	France	13009
21	Hôpital Nord Marseille	Marseille	France	13915
22	Centre Azuréen de Cancérologie	Mougins	France	06250
23	ORACLE - Centre d'Oncologie de Gentilly	Nancy	France	54000
24	Hôpital Privé du Confluent	Nantes	France	44277
25	Centre ONCOGARD - Institut de cancérologie du Gard	Nîmes	France	30029
26	CHR Orléans	Orléans	France	45100
27	Hôpital cochin	Paris	France	75014
28	Hôpital Européen Georges Pompidou	Paris	France	75015
29	Groupe Hospitalier Diaconesses - Croix Saint-Simon	Paris	France	75020
30	Hôpital Tenon	Paris	France	75020
31	HCL - Centre Hospitalier Lyon Sud (Hospices Civils de Lyon)	Pierre-Bénite	France	69495
32	Centre CARIO - HPCA	Plérin	France	22190
33	CHU de Poitiers - Hôpital de la Milétrie	Poitiers	France	86021
34	Institut Jean Godinot	Reims	France	51100
35	Centre Eugène Marquis	Rennes	France	35042
36	Centre Henri Becquerel	Rouen	France	76038
37	ICO - Centre René Gauducheau	Saint-Herblain	France	44800
38	CHU de Saint-Etienne - Pôle de Cancérologie	Saint-Priest-en-Jarez	France	42055
39	ICANS - Institut de cancérologie Strasbourg Europe	Strasbourg	France	67033
40	Institut Claudius Regaud	Toulouse	France	31059
41	CHU Tours - Hôpital Bretonneau	Tours	France	37044
42	Gustave Roussy	Villejuif	France	94805