Please select the eligibility criteria that correspond to the clinical trial below.
Title: Part 1: AVANOVA1 - A Phase I Study to Evaluate the Safety and Tolerability of Bevacizumab-niraparib Combination Therapy and Determine the Recommended Phase 2 Dose (RP2D) in Women With Platinum-sensitive Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer Part 2: AVANOVA2 - A Two-arm, Open-label, Phase II Randomized Study to Evaluate the Efficacy of Niraparib Versus Niraparib-bevacizumab Combination in Women With Platinum-sensitive Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer.
Brief Summary: Part 1 (Phase 1): safety and tolerability of bevacizumab-Niraparib combination Part 2 (Randomized Phase 2): to compare Progression-Free Survival (PFS)

PARP inhibitors are active as monotherapy to treat patients with recurrent ovarian cancer; the strongest activity being observed in the platinum sensitive, gBRCAmut subgroup as well as in gBRCAwt, HRD population but also in HRD negative disease.

In the same population there is level one evidence that bevacizumab is beneficial. And a phase two randomized study has indicated that combination of a PARP inhibitor with anti-angiogenic drug is superior to PARP inhibitor alone.

The question is:

Is niraparib combined with bevacizumab superior to niraparib? The comparison of tolerability and efficacy of niraparib-bevacizumab combination against niraparib.


Options:
A: Inclusion Criteria:

* Case reported in the World Health Organization (WHO, also called VigiBase) or French database of individual safety case reports at the time of the extraction,
* Patients treated with at least 1 PARPi (with ATC classification system): olaparib (ATC L01XX46), niraparib (ATC L01XX54), rucaparib (ATC L01XX55), talazoparib (ATC L01XX60), veliparib (none).

Exclusion Criteria:

* Chronology not compatible between the PARPi and adverse event (MDS/AML)
B: Inclusion Criteria:

* Histologically confirmed malignant advanced solid tumour, which is refractory to standard therapies (except Group 8 patients who must not be platinum refractory) or for which no suitable effective standard therapy exists
* Patients must have adequate organ and bone marrow function measured within 7 days prior to administration of study treatment
* Female patients must have evidence of non-child bearing status: negative urine or serum pregnancy test within 7 days of study treatment for women of child bearing, or postmenopausal status

Exclusion Criteria:

* Patients receiving chemotherapy, radiotherapy (except for palliative reasons) or any other anti-cancer therapy within 4 weeks of the last dose prior to study entry. Patients may continue the use of biphosphonates for bone metastases and corticosteroids
* Patients with symptomatic uncontrolled brain metastases
* Major surgery within 2 weeks of starting study and patients must have recovered from any effects of any major surgery
* Patients who are platinum refractory (Group 8 only)
* Patients with myelodysplastic syndrome/acute myeloid leukaemia (Group 8 only).
C: Inclusion Criteria:

* Capable of providing signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in the Clinical Study Protocol (CSP).
* Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses.
* Female ≥18 years of age at the time of signing the ICF.
* Eastern Cooperative Oncology Group performance status 0 to 1 within 28 days of randomization.
* Participants with relapsed histologically confirmed diagnosis of high grade epithelial ovarian cancer (including primary peritoneal and/or fallopian tube cancer), with disease relapse on or after completion of PARPi maintenance therapy and who have not received any intervening systemic treatment since discontinuation of PARPi (this excludes the platinum based chemotherapy received during Screening Part 1 of this study).
* A minimum of 6 months of prior PARPi treatment received in the maintenance setting for PSR ovarian cancer (a minimum of 12 months is required if the participant received PARPi maintenance following first line chemotherapy). If the prior PARPi used was olaparib then participants must have received treatment without significant toxicity or the need for a permanent dose reduction.
* Disease relapse in the second line (first relapse) or third line (second relapse) setting.
* Able to provide and consent to the collection of a contemporaneous tumor tissue biopsy and blood sample.
* Able to provide a Formalin Fixed Paraffin Embedded archival tumour tissue block from the time of primary tumour diagnosis (taken ideally prior to receiving any systemic treatment, and definitely prior to first PARPi treatment) for prospective Breast cancer susceptibility gene (BRCA) status testing. If tumour blocks are unavailable, tissue sections are acceptable with a minimum requirement of at least 20 unstained sections on uncharged slides without cover slips. Fine needle aspirates are not acceptable.
* Where the patient has previously been tested for germline or somatic BRCA alterations using a verified and well-validated test in line with local regulations, performed in a locally accredited laboratory (eg, College of American Pathologists/Clinical Laboratory Improvement Amendments laboratory, where available), and signed consent to provide a copy of the BRCA report.
* Platinum-sensitive disease at the time of disease relapse, i.e, platinum-treatment free survival of greater than 6 months as defined by the Gynecological Cancer Intergroup (Wilson et al 2017).
* For the platinum-based chemotherapy course received following pre screening (Part 1) and prior to entering the main screening (Part 2).
* Any prior palliative radiation must have been completed at least 7 days prior to the start of study drugs, and participants must have recovered from any acute adverse effects prior to the start of study treatment.
* Normal organ and bone marrow function measured within 28 days prior to randomization.
* Participant is willing and able to comply with the CSP for the duration of the study including undergoing treatment and scheduled visits and examinations.
* Participants must have a life expectancy of ≥16 weeks.
* Participants must be able to swallow tablets whole.
* For inclusion in the optional (deoxyribonucleic acid) genetics research, study participants must fulfil the following criterion:

Provide informed consent for the genetic sampling and analyses. If a participant declines to participate in the genetics research, there will be no penalty or loss of benefit to the participant. A participant who declines genetics research participation will not be excluded from any other aspect of the main study.

* Participant's body weight must be \>30 kg.
* Postmenopausal or evidence of non-childbearing status for women of childbearing potential.
* Women of childbearing potential and their partners, who are sexually active, must agree to the use of 2 highly effective forms of contraception in combination from the signing of the informed consent (Screening Part 1), throughout the period of taking study treatment and for at least 6 months after the last dose of study drug(s).

Exclusion Criteria:

* Participants who have had drainage of their ascites during the final 2 cycles of their last chemotherapy regimen or during the period between completion of chemotherapy and first dose of study treatment.
* Participants with current signs or symptoms of bowel obstruction, including sub-occlusive disease, related to underlying disease.
* History of leptomeningeal carcinomatosis.
* Participants with symptomatic uncontrolled brain metastases.

  1. A scan to confirm the absence of brain metastases is not required.
  2. Participants whose brain metastases have been treated may participate provided they show radiographic stability. In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable (Common Terminology Criteria for Adverse Events \[CTCAE\] Grade \<2) either, without the use of steroids, or are stable on a steroid dose of ≤10 mg/day of prednisone or its equivalent and stable on anti convulsants if required for at least 14 days prior to the start of treatment.
  3. Participants with spinal cord compression are not eligible unless considered to have received definitive treatment for this and have evidence of clinically SD for \>28 days and have not received steroid treatment for at least 14 days prior to the start of study treatment.
* History of another primary malignancy except for:

  1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence;
  2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
  3. Adequately treated carcinoma in situ without evidence of disease.
* Major surgical procedures (as defined by the investigator) ≤28 days of beginning study treatment, or minor surgical procedures ≤7 days. No waiting period required following port a cath or other central venous access placement.
* Persistent toxicities (≥CTCAE Grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE Grade 2 peripheral neuropathy. Note: participants with signs of ongoing complications from radiation therapy are not eligible for this study.
* Participants with myelodysplastic syndrome (MDS) /acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
* Resting electrocardiogram indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator, or participants with congenital long QT syndrome.
* Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
* History of allogeneic organ transplantation including previous allogeneic bone marrow transplant or double umbilical cord blood transplantation.
* History of active primary immunodeficiency.
* Active infection including tuberculosis (TB), hepatitis B (known positive hepatitis B virus \[HBV\] surface antigen \[HBsAg\] result), hepatitis C (HCV), or human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies). Participants with a past or resolved HBV infection are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid.
* Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations.
* Current dependency on total parenteral nutrition or intravenous (iv) fluid hydration.
* Whole blood transfusions in the last 120 days prior to entry to the study.
* Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days of Cycle 1, Day 1 is not permitted. The participant can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 5 days prior to study treatment.
* Participation in another clinical study with an IP during the chemotherapy course immediately prior to randomisation or during the course of the study.
* Previous treatment with ceralasertib or other ataxia telangiectasia and Rad3-related protein, Checkpoint kinase 1 or deoxyribonucleic acid damage response inhibitor (excluding PARPi).
* Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer) prior to randomization. The minimum washout period for immunotherapy and bevacizumab shall be 42 days.
* Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment.
* Concomitant use of known strong cytochrome P450 (CYP) 3A inhibitors or moderate CYP3A inhibitors. The required washout period prior to starting study treatment is 2 weeks.
* Concomitant use of known strong CYP3A inducers or moderate CYP3A inducers. The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
* Involvement in the planning and/or conduct of the study (applies to Sponsor staff and/or staff at the study site).
* Previous randomization in the present study.
* Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.
* Pregnant or lactating women.
D: Inclusion Criteria:

A patient will be eligible for inclusion only if all of the following criteria are fulfilled:

1. Recurrent platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer (platinum sensitivity defined as no recurrence within 6 months of last receipt of platinum/chemotherapy).
2. High-grade serious or high-grade endometrioid histology.
3. Patient consents to perform HRD test.

   * Patients with known BRCA status: BRCA positive patients must submit the tissue for HRD test, though these patients need not to wait for HRD test results and can be randomized in HRD positive stratum.
   * If tumor tissue is not sufficient to perform HRD test: these patients shall be randomized in HRD negative stratum as HRD unknown.
4. Prior line of therapy: Patients must have received platinum-containing therapy for primary disease.

   * No limits on number of platinum-based therapies. Population of patients who has previously received ≥ 3 lines of therapy for relapsed disease will be capped at 40%.
   * Up to one non-platinum-based line of therapy in recurrent setting.
   * Patients who are treated with bevacizumab just prior to entering in the trial must not have progressed under or within 3 months after bevacizumab.
   * Patients may have participated in a PARP inhibitor trial as first-line maintenance therapy and have not progressed within 3 months after PARP/placebo. Patients who received PARP inhibitor after relapse (definitive or maintenance therapy) are not eligible.
5. Target group: Age 18+
6. Histological confirmed ovarian, fallopian tube or peritoneal cancers
7. Patients must give informed consent
8. Patients may have undergone primary or interval debulking surgery
9. Patients may have received bevacizumab though no other prior use of anti-angiogenic therapy
10. Patients may have received a PARP inhibitor as first-line maintenance therapy.
11. Patients must have disease that is measurable according to RECIST or assessable according to the GCIG criteria
12. The patient agrees to complete PROs (QoL questionnaire) during study treatment AND at one additional time point 8 weeks following progression of disease
13. ECOG performance status 0-2
14. Adequate organ function

    * Absolute neutrophil count (ANC) ≥1,5 x 109/L
    * Platelets \>100 x 109/L
    * Hemoglobin ≥ 9g/dl
    * Serum creatinine ≤1.5x upper limit of normal (ULN) or calculated creatinine clearance ≥50mL/min using Cockcroft-Gault formula
    * Total bilirubin ≤1.5x ULN
    * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN unless liver metastases are present, in which case they must be ≤5x ULN.
15. Able to take oral medications
16. Life expectancy of at least 12 weeks
17. Patients must fulfill all inclusions criteria and according to investigator fit to receive niraparib and/or bevacizumab.
18. Women of childbearing potential must use adequate birth control for the duration of study participation

Exclusion Criteria:

A patient will not be eligible for inclusion if any of the following criteria are fulfilled:

1. Ovarian sarcomas, small cell carcinoma with neuroendocrine differentiation, non-epithelial cancers and cancer types not mentioned in the inclusion criteria
2. Concurrent cancer therapy
3. Concurrent treatment with an investigational agent or participation in another clinical trial
4. Major injuries or surgery within the past 21 days prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period
5. Previous malignant disease: patients are not eligible for the study if diagnosis, detection or treatment of invasive cancer (other than ovarian cancer; with the exception of basal or squamous cell carcinoma of the skin that was definitively treated) was detected within 2 years prior to randomization
6. Active infections or other serious underlying significant medical illness, abnormal laboratory finding or psychiatric illness/social situation that would, in the Investigator's judgment, makes the patient inappropriate for this study
7. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug
8. History of bowel obstruction, including sub-occlusive disease, related to the underlying disease and history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess. Evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction
9. Known contraindications to PARP inhibitors or VEGF directed therapy
10. Known uncontrolled hypersensitivity to the investigational drugs
11. History of major thromboembolic event defined as:

    * Uncontrolled pulmonary embolism (PE)
    * Deep venous thrombosis (DVT)
    * Other related conditions, though patients with stable therapeutic anticoagulation for more than three months prior randomization are eligible for this study. This also apply to PE \& DVT.
12. History of a cerebral vascular accident, transient ischemic attack or subarachnoid hemorrhage within the past 3 months
13. History of clinically significant hemorrhage in the past 3 months
14. Uncontrolled and/or symptomatic CNS metastasis or leptomeningeal carcinomatosis (Dexamethasone/prednisone therapy will be allowed if administered as stable dose for at least one month prior randomization)
15. Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within 6 months prior to randomization, congestive heart failure \> NYHA III, severe peripheral vascular disease, QT prolongation \>470 msec ,clinically significant pericardial effusion
16. Pregnancy or breastfeeding. Patients with preserved reproductive capacity, unwilling to use a medically acceptable method of contraception for the duration of the trial and for 3 months afterwards.
17. Radiographic evidence of cavitation or necrotic tumors with invasion of adjacent major blood vessels
18. Active or chronic hepatitis C and/or B infection
19. Persistence of clinically relevant therapy related toxicity from previous chemotherapy
20. Proteinuria as demonstrated by: (a) urine protein: creatinine (UPC) ratio \>/= 1.0 at screening OR (b) urine dipstick for proteinuria \>/=2+ (patients discovered to have \>/=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hr urine collection and must demonstrate \</=1g of protein in24 hours to be eligible
21. Patients must not have any known history of MDS
22. Patients must not have known persistent (\> 4 weeks) ≥ Grade 2 hematological toxicity from prior cancer therapy
23. Patients must not have known ≥ Grade 3 thrombocytopenia or anemia with the last chemotherapy regimen.

Answer: D