Niraparib with BeVAcizumab After Complete CytoreductioN in Patients with OvArian Cancer

Phase 2

Recruiting

• Conditions: Ovarian Cancer
• Interventions: Drug: Chemotherapy; Drug: Niraparib; Drug: Bevacizumab-Awwb

• Registration Number: NCT05183984
• Lead Sponsor: ARCAGY/ GINECO GROUP

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.

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 Timeline

• Study First Submitted: 2021-11-22
• Study First Submitted QC: 2022-01-05
• Study First Posted: 2022-01-11
• Study Start: 2022-02-01
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-15
• Last Update Posted: 2024-10-16
• Primary Completion: 2027-02
• Study Completion: 2030-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 390

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).

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

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

  8. 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).

    15. 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.

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

    17. 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.

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

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

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

    21. 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.

    22. 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.

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

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

    25. 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).

    26. 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ARM A: carboplatin/paclitaxel + niraparib	Chemotherapy	carboplatin AUC 5-6 + paclitaxel 175 mg/m² q3w, 5 cycles, followed by niraparib 200\* or 300 mg/d for 2 years.
ARM B: carboplatin/paclitaxel/bevaziumab + niraparib/bevacizumab	Chemotherapy	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.
ARM A: carboplatin/paclitaxel + niraparib	Niraparib	carboplatin AUC 5-6 + paclitaxel 175 mg/m² q3w, 5 cycles, followed by niraparib 200\* or 300 mg/d for 2 years.
ARM B: carboplatin/paclitaxel/bevaziumab + niraparib/bevacizumab	Bevacizumab-Awwb	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.
ARM B: carboplatin/paclitaxel/bevaziumab + niraparib/bevacizumab	Niraparib	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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

Trial Locations

Locations (87)

Clinique Victor Hugo; 🇫🇷 Le Mans, France

CHU Montpellier - Hôpital Saint Eloi; 🇫🇷 Montpellier, France

Hôpital Saint-Joseph; 🇫🇷 Paris, France

CH Valence; 🇫🇷 Valence, France

Firenze-Careggi; 🇮🇹 Firenze, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori; 🇮🇹 Milano, Italy

Istituto Europeo di Oncologia (IEO); 🇮🇹 Milano, Italy

Ospedale San Gerardo Monza; 🇮🇹 Monza, Italy

Presidio Ospedaliero di Sondrio; 🇮🇹 Sondrio, Italy

Cancer Institute Hospital Of JFCR; 🇯🇵 Tokyo, Ariake, Koto, Japan

National Cancer Center Hospital East; 🇯🇵 Kashiwanoha, Chiba, Japan

Kurume University Hospital Clinical Research Center; 🇯🇵 Kurume, Fukuoka, Japan

University of Tsukuba Hospital; 🇯🇵 Tsukuba, Ibaraki-Pref, Japan

Niigata Cancer Center Hospital; 🇯🇵 Niigata, Niigata-ken, Japan

Okayama University Hospital; 🇯🇵 Kita-ku, Okayama, Japan

Jichi Medical UH; 🇯🇵 Shimotsuke, Tochigi-ken, Japan

Ehime University Hospital; 🇯🇵 Ehime, Toonshi, Japan

Yamagata University Hospital; 🇯🇵 Yamagata, Japan

Samsung Medical Center; 🇰🇷 Seoul, Gangnam-gu, Korea, Republic of

National Cancer Center; 🇰🇷 Seoul, Gyeonggi-do, Korea, Republic of

National University Hospital; 🇰🇷 Seoul, Jongno-gu, Korea, Republic of

Severance Hospital; 🇰🇷 Seoul, Seodaemun-gu, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Songpa-gu, Korea, Republic of

National University Hospital (NUH); 🇸🇬 Singapore, Singapore

National Cancer Centre Singapore; 🇸🇬 Singapore, Singapore

Coruña University Hospital (CHUAC); 🇪🇸 A Coruña, Spain

Hospital del Mar; 🇪🇸 Barcelona, Spain

Hospital Universitari Dexeus; 🇪🇸 Barcelona, Spain

Hospital San Pedro de Alcantara; 🇪🇸 Cáceres, Spain

Hospital Clínico Universitario Virgen de la Arrixaca; 🇪🇸 El Palmar, Murcia, Spain

Hospital Universitario de Jerez; 🇪🇸 Jerez de la Frontera, Spain

Clínica Universidad de Navarra; 🇪🇸 Madrid, Spain

Hospital Universitario La Paz; 🇪🇸 Madrid, Spain

Hospital Universitario Puerta de Hierro; 🇪🇸 Madrid, Spain

Hospital Virgen de la Victoria; 🇪🇸 Málaga, Spain

Hospital Universitario Central de Asturias; 🇪🇸 Oviedo, Spain

Clinica Universidad de Navarra.; 🇪🇸 Pamplona, Spain

Complejo Hospitalario de Navarra; 🇪🇸 Pamplona, Spain

CHU de Santiago de Compostela; 🇪🇸 Santiago de Compostela, Spain

Hospital Universitari MutuaTerrassa; 🇪🇸 Terrassa, Spain

Fundación Investigación Clínico de Valencia.; 🇪🇸 Valencia, Spain

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

CHU de Dijon - Bourgogne; 🇫🇷 Dijon, France

Centre Georges François Leclerc; 🇫🇷 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

Hôpital Privé Jean Mermoz; 🇫🇷 Lyon, France

HCL - Hôpital de la Croix Rousse; 🇫🇷 Lyon, France

Institut Paoli Calmettes; 🇫🇷 Marseille, France

Hôpital Nord Marseille; 🇫🇷 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 Pitié Salpêtrière; 🇫🇷 Paris, France

Hôpital cochin; 🇫🇷 Paris, France

Institut Mutualiste Montsouris; 🇫🇷 Paris, France

Hôpital Européen Georges Pompidou; 🇫🇷 Paris, France

Groupe Hospitalier Diaconesses - Croix Saint-Simon; 🇫🇷 Paris, France

Hôpital Tenon; 🇫🇷 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, France

Saitama Medical University International Medical Center; 🇯🇵 Saitama, Japan