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:

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.
B: Inclusion Criteria:

1. Patients with histologically confirmed epithelial ovarian cancer, primary peritoneal carcinomatosis or fallopian tube cancer
2. Patients must have platinum resistant (relapse-free interval \< 6 months of a platinum-containing primary or secondary therapy) or platinum refractory (progression during primary or secondary platinum treatment) disease defined by measurable disease according to RECIST or elevated CA-125 level according the GCIG-criteria.

   Definition of relapse: Demonstration of measurable or non-measurable tumour according to RECIST criteria by an imaging procedure (where applicable before relapse surgery) or increase in the tumour marker CA-125 to twice the upper laboratory value of normal for the hospital or histological confirmation of tumour relapse by biopsy or surgery.
3. No more than 2 prior treatment regimens for recurrent epithelial ovarian cancer.
4. Elevated CA-125-value before study entry in order to assess the response according the GCIG-criteria (see below). Patients without elevated CA-125 may be enrolled if they show a measurable or not-measurable disease (according RECIST) evaluated by imaging techniques (measurable disease - at least one unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan) or histologically or cytologically confirmed relapse
5. ECOG Performance Status of 0 or 1
6. ≥ 18 years age
7. The patient must be recovered from a prior operation. The operation must be performed at least 4 weeks prior to start of study drug,
8. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening

   * Hemoglobin ≥ 9.0 g/dl
   * Leucocyte count ≥ 3.000/micro liter
   * Absolute neutrophil count (ANC) major than 1.500/micro liter
   * Platelet count ≥ 100.000/micro liter
   * PT-INR/PTT \< 1.5 x upper limit of normal \[Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists\].
   * Total bilirubin \< 1,0 times the upper limit of normal
   * ALT and AST \< 2,5 x upper limit of normal (\< 5 x upper limit of normal for patients with liver involvement of their cancer); Alkaline phosphatase \< 4 x ULN
   * Calculated creatinine clearance ≥ 50 ml/min or serum creatinine ≤ 1,2 x upper limit of institutional values (according to Cockcroft and Gault)
9. Life expectancy of at least 12 weeks
10. Signed and dated written informed consent before the start of specific protocol procedures.

Exclusion Criteria:

1. History of cardiac disease: congestive heart failure \>NYHA class 2; active coronary artery disease (CAD) or myocardial infarction within the past 6 months (MI more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled arterial hypertension with systolic blood pressure \>160 mmHg or diastolic blood pressure \> 90 mm Hg despite optimal treatment
2. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors \[Ta, Tis \& T1\] or any cancer curatively treated \> 5 years prior to study entry
3. Prior radiological or clinical evidence of CNS metastases including previously treated, resected, or asymptomatic brain lesions or leptomeningeal involvement by head CT scan or MRI
4. Known or suspected hypersensitivity reaction to topotecan or any ingredient of topotecan or sorafenib or any ingredient of sorafenib
5. Active clinically serious infections (\> grade 2 NCI-CTC version 3.0)
6. History of HIV infection or chronic hepatitis B or C
7. History of organ allograft
8. Patients with history of colon perforation
9. Patients with history of colitis or neutropenia colitis
10. Patients with evidence or history of bleeding diathesis
11. Serious non healing wound, fracture or ulcer
12. Patients undergoing renal dialysis
13. Patients unable to swallow oral medications
14. Significant disease which, in the investigator's opinion, would exclude the patient from the study
15. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
16. Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
17. Medical or psychological conditions that would not permit the subject to complete the study or sign informed consent
18. Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
19. Legal incapacity or limited legal capacity
20. Participation in another clinical study with experimental therapy within the 30 days before start of treatment
21. Subjects housed in an institution on official or legal orders.

    Excluded therapies and medications, previous and concomitant:
22. Patients with prior therapy containing topotecan
23. Patients with prior therapy containing Avastin or other VEGFR TK1
24. Any other anticancer chemotherapy or immunotherapy or investigational drug therapy outside of this trial during the study or within 4 weeks prior to study entry.
25. Radiotherapy during study or within 4 weeks prior to start of study drug and prior radiotherapy of \> 25% of the bone marrow (exception: palliative radiotherapy of non-target lesions or pain therapy or local bone irradiation)
26. Autologous bone marrow transplant or stem cell rescue within 4 months of study
C: Inclusion Criteria:

* Participants receiving a histologic diagnosis of epithelial ovarian cancer (EOC), peritoneal primary carcinoma, or fallopian tube cancer.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
* Life expectancy of at least 12 weeks.
* Adequate hematological, liver, renal and neurologic functions.
* For participants who receive therapeutic anticoagulation: stable anticoagulant regimen.
* Enrollment between 1 and 12 weeks after initial surgery is performed for the combined purpose of diagnosis, staging, and cytoreduction

Exclusion Criteria:

* Current diagnosis of borderline epithelial ovarian tumor or recurrent invasive epithelial ovarian, primary peritoneal, or fallopian tube cancer treated with surgery only.
* Prior radiotherapy to any portion of the abdominal cavity or pelvis.
* Prior chemotherapy for any abdominal or pelvic tumor, including neoadjuvant chemotherapy for ovarian, primary peritoneal, or fallopian tube cancer.
* Any prior targeted therapy (including, but not limited to, vaccines, antibodies, or tyrosine kinase inhibitors) or hormonal therapy for management of their epithelial ovarian or peritoneal primary cancer.
* Synchronous primary endometrial cancer.
* Have a prior history of primary endometrial cancer, except: Stage not greater than Stage IB; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell, or other International Federation of Gynecological Oncologists (FIGO) Grade 3 lesions.
* Cancer present within the last 5 years with the exception of non-melanoma-related skin cancers and other specific malignancies or whose previous cancer treatment contraindicates study treatment.
* Active hepatitis B virus (HBV) infection (chronic or acute) or active hepatitis C virus (HCV) infection.
* Serious non-healing wounds, ulcers, or bone fractures.
* Patients with clinically significant cardiovascular disease.
* Have known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
* Have known sensitivity to any component of paclitaxel.
* Undergo major surgical procedure within 28 days prior to randomization or anticipated during the course of the study.
* Have core biopsy or other minor surgical procedures within 7 days prior to the first dose of bevacizumab/placebo.
* History or evidence of thrombotic disorders within the last 6 months prior to enrollment.
D: Inclusion Criteria:

1. Histologically confirmed diagnosis of epithelial ovarian carcinoma or fallopian tube carcinoma or primary peritoneal carcinoma
2. First disease recurrence \>6 months after first-line platinum-based chemotherapy
3. Patients with measurable or non-measurable disease (RECIST v1.1) or CA 125 assessable disease (GCIG criteria) or histological proven diagnosis of relapse
4. In case of cytoreductive surgery for recurrence, patients must be able to commence cytotoxic chemo-therapy within 8 weeks after cytoreductive surgery
5. ECOG PS 0-2
6. Absolute Neutrophil Count \>= 1.5 x 10\^9/L; Platelets \>= 100 x 10\^9/L; Hemoglobin \>= 9.5 g/dL
7. Patients not receiving anticoagulant medication who have an International Normalized Ratio \<= 1.5 and an Activated ProThrombin Time \<= 1.5 x ULN
8. Serum bilirubin \<= 2 x ULN; Serum transaminases \<= 2.5 x ULN (\<= 5 x ULN in the presence of liver metastasis)
9. Serum creatinine \< 1.6 mg/dL or creatinine clearance \>= 40 mL/min; Glomerular filtration rate \> 40 ml/min (estimates based on the Cockroft-Gault or Jelliffe formula); Urine dipstick for proteinuria \< 2+. If urine dipstick is \>= 2+, 24 hour urine collection must demonstrate \<= 1 g of protein in 24 hours
10. Normal blood pressure or adequately treated and controlled hypertension (either systolic BP ≤ 140 mmHg and/or diastolic BP ≤ 90 mmHg)

Exclusion Criteria:

1. Ovarian tumors of low malignant potential
2. Malignancies other than ovarian cancer within 5 years prior to randomization
3. Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period
4. Any previous radiotherapy to the abdomen or pelvis
5. Known hypersensitivity to used chemotherapeutic agents in this trial and bevacizumab and its excipients, chinese hamster ovary cell products or other recombinant human or humanised antibodies
6. Current or recent chronic use of aspirin \> 325 mg/day
7. Surgery (including open biopsy) within 4 weeks prior to anticipated first dose of Bevacizumab
8. History of VEGF therapy related abdominal fistula or gastrointestinal perforation
9. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease
10. Patients with evidence of abdominal free air not explained by paracentesis or recent surgical procedure
11. Previous Cerebro-Vascular Accident , Transient Ischaemic Attack or Sub-Arachnoid Haemorrhage
12. Prior history of hypertensive crisis or hypertensive encephalopathy
13. Clinically significant disease, including: myocardial infarction or unstable angina within ≤ 6 months of randomization; New York Heart Association (NYHA) \>= grade 2 Congestive Heart Failure; poorly controlled cardiac arrhythmia despite medication; peripheral vascular disease grade \>= 3
14. LVEF defined by ECHO/MUGA below the institutional lower limit of normal
15. Significant traumatic injury during 4 weeks prior to randomization
16. Current brain metastases or spinal cord compression
17. History or evidence upon neurological examination of central nervous system disease
18. Non-healing wound, active ulcer or bone fracture
19. History or evidence of thrombotic or hemorrhagic disorders within 6 months prior to randomization
20. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic coagulation)
21. Fertile woman of childbearing potential not willing to use adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the duration of the trial and at least 6 months afterwards
22. Pregnant or lactating women
23. Requirement of therapeutic anticoagulation using marcumar, warfarin or PTT-prolonging heparin

Answer: A