Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized Pilot Trial of Oral Cyclophosphamide Versus Oral Cyclophosphamide With Celecoxib for Recurrent or Persistent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
Brief Summary: RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cyclophosphamide together with celecoxib may kill more tumor cells.

PURPOSE: This randomized phase II trial is studying how well giving cyclophosphamide together with celecoxib works compared to cyclophosphamide alone in treating patients with recurrent or persistent ovarian epithelial, fallopian tube, or primary peritoneal cancer.


Options:
A: Inclusion

* Patients with recurrent or residual epithelial ovarian, Fallopian tube, or primary papillary peritoneal cancer, which has been histologically confirmed regardless of prior treatment
* Patients with measurable disease or rising CA-125 to levels at least twice normal (the CA-125 increase must be documented by two independent measurements at least 4 weeks apart)
* Patient must have adequate renal function documented by a creatinine \< 1.5
* Patients must have adequate bone marrow function as evidenced by an absolute neutrophil count of \> 1.5 x 10\^9/L and a platelet count \> 100 x 10\^9/L
* Patients must have a Karnofsky performance status of 60-100%
* Patient must be capable of understanding the nature of the trial and must give written informed consent
* Patients must have life expectancy of at least three months
* Patients with brain metastases which at the time of study enrollment are controlled and do not require treatment with corticosteroids are eligible

Exclusion

* Patients who have had radiotherapy or chemotherapy within three weeks prior to anticipated first day of dosing (patients must be fully recovered from the acute effects of any prior chemotherapy or radiotherapy
* Patient with unstable or severe intercurrent medical conditions or active, uncontrolled infection
* Patients with history of bleeding peptic ulcer within last 3 months
* Patients undergoing therapy with other investigational agents (patients must have recovered from all acute effects of previously administered investigational agents and sufficient time must have elapsed since last administration to ensure the drug interactions not occur during this study
* Patients who are allergic to sulfa drugs
* Pregnant women will be excluded from this study due to the potential of harm to the fetus
* Patients with clinically significant cardiovascular disease (e.g. uncontrolled hypertension, myocardial infarction unstable angina), New York heart association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or grade II or greater peripheral vascular disease within 1 year prior to study entry
* Subjects with hypertension are eligible if their blood pressure as been normal while on a stable dose of medication for at least one year
B: Inclusion Criteria:

* Signed written informed consent obtained prior to initiation of any study specific procedures and treatment as confirmation of the patients awareness and willingness to comply with the study requirements
* Primary diagnosis is confirmed by specialized pathology review (Germany only)
* Females aged ≥ 18 years
* Histologically confirmed, newly diagnosed

  * Epithelial ovarian carcinoma
  * Fallopian tube carcinoma
  * Primary peritoneal carcinoma AND FIGO stage IIb - IV (all grades and all histological types)
* Patients should have already undergone surgical debulking, by a surgeon experienced in the management of ovarian cancer, with the aim of maximal surgical cytoreduction according to the GCIG Conference Consensus Statement. There must be no planned surgical debulking prior to disease progression. Patients with stage III and IV disease in whom initial surgical debulking was not appropriate or possible will still be eligible providing

  * the patient has a histological diagnosis and
  * debulking surgery prior to disease progression is not foreseen
* Patients must be able to commence cytotoxic chemotherapy within 8 weeks of cytoreductive surgery. The first dose of bevacizumab can be omitted in both arms if the investigator decides to start chemotherapy within 4 weeks of surgery.
* ECOG 0-2
* Life expectancy \> 3 months
* Adequate bone marrow function (within 14 days prior to randomization)

  * ANC ≥ 1.5 x 10\^9/L
  * PLT ≥ 100 x 10\^9/L
  * Hb ≥ 9 g/dL (can be post-transfusion)
* Adequate coagulation parameters (within 14 days prior to randomization)

  * Patients not receiving anticoagulant medication who have an INR ≤ 1.5 and an aPTT ≤ 1.5 x ULN
  * The use of full-dose oral or par-enteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to institution medical standard) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of randomization.
* Adequate liver function (within 14 days prior to randomization)

  * Serum bilirubin ≤ 1.5 x ULN
  * Serum transaminases ≤ 2.5 x ULN
* Urine dipstick for proteinuria \< 2+. If urine dipstick is ≥ 2+, 24 hour urine must demonstrate ≤ 1 g of protein in 24 hours
* Adequate postoperative GFR \> 40 ml/min (estimates based on the Cockroft-Gault or Jelliffe formula are sufficient)

Exclusion Criteria:

* Non-epithelial origin of the ovary, the fallopian tube or the peritoneum
* Borderline tumours (tumours of low malignant potential) and FIGO stage Ia - IIa tumours
* Planned intraperitoneal cytotoxic chemotherapy
* Prior systemic anti-cancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy)
* Surgery (including open biopsy) within 4 weeks prior to anticipated first dose of bevacizumab (allowing for the fact that bevacizumab can be omitted from the first cycle of chemotherapy). It is strongly recommended that an interval of 7 days is left between the insertion of any central venous access devices (CVADs) and the onset of bevacizumab treatment.
* Any planned surgery during the study treatment period plus 4 additional weeks to allow for bevacizumab clearance
* Uncontrolled hypertension (sustained elevation of BP systolic \> 150mmHg and/or diastolic \> 100mmHg despite antihypertensive therapy)
* Any previous radiotherapy to the abdomen or pelvis
* Significant traumatic injury during 4 weeks preceding the potential first dose of bevacizumab
* 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
* Previous Cerebro-Vascular Accident (CVA), Transient Ischaemic Attack (TIA) or Sub-Arachnoid Haemorrhage (SAH) within 6 months prior to randomization
* 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 study duration and at least 6 months afterwards
* Pregnant or lactating women
* Treatment with other investigational agents, or participation in another clinical trial testing a drug within the past 4 weeks before start of therapy concomitantly with this trial
* Malignancies other than ovarian cancer within 5 years prior to randomization, except for adequately treated

  * carcinoma in situ of the cervix
  * and/or basal cell skin cancer
  * and/or non-melanomatous skin cancer
  * carcinoma in situ of the breast
  * and/or early endometrial carcinoma as specified below. Patients may have received previous adjuvant chemotherapy for other malignancies e.g. breast or colorectal carcinoma if diagnosed over 5 years ago with no evidence of subsequent recurrence.
* Patients with synchronous primary endometrial carcinoma, or a past history of primary endometrial carcinoma, are excluded unless ALL of the following criteria for describing the endometrial carcinoma are met

  * Disease stage FIGO stage ≤ IA (tumour invades less than one half of the myometrium)
* Known hypersensitivity to bevacizumab and its excipients, Chinese hamster ovary cell products or other recombinant human or humanised antibodies
* Non healing wound, active ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require 3 weekly wound examinations
* History or evidence of thrombotic or hemorrhagic disorders within 6 months prior to randomization
* Clinically significant cardiovascular disease, including

  * Myocardial infarction or unstable angina within 6 months of randomization
  * NYHA ≥ Grade 2 Congestive Heart Failure (CHF)
  * Poorly controlled cardiac arrhythmia despite medication (patients with rate-controlled atrial fibrillation are eligible)
  * Grade ≥ 3 peripheral vascular disease (i.e. symptomatic and interfering with activities of daily living requiring repair or revision)
* Current or recent (within 10 days prior to randomization) chronic use of aspirin \> 325 mg/day
* Pre-existing sensory or motor neuropathy ≥ Grade 2
* Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
C: Inclusion Criteria:

* Female patients with histologically diagnosed serous ovarian cancer or recurrent serous ovarian cancer.
* Patients must have completed at least 2 previous courses of platinum containing therapy; the patient must have been platinum sensitive to the penultimate chemo regimen.
* For the last chemotherapy course prior to enrolment on the study, patients must have demonstrated an objective stable maintained response (partial or complete response) and this response needs to be maintained until completion of chemotherapy.
* Patients must be treated on the study within 8 wks of completion of their final dose of the platinum containing regimen.

Exclusion Criteria:

* Previous treatment with PARP inhibitors including AZD2281
* Patients with low grade ovarian carcinoma.
* Patients who have had drainage of their ascites during the final 2 cycles of their last chemotherapy regimen prior to enrolment on the study
* Patients receiving any chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study entry (or a longer period depending on the defined characteristics of the agents used).
D: Inclusion Criteria:

* Patients must be ≥ 18 years of age.

  * Female patients with histologically diagnosed relapsed high grade serous ovarian cancer (including primary peritoneal and / or fallopian tube cancer) or high grade endometrioid cancer.
  * Documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function).
  * Patients who have received at least 2 previous lines of platinum containing therapy prior to randomisation

For the penultimate chemotherapy course prior to enrolment on the study:

• Patient defined as platinum sensitive after this treatment; defined as disease progression greater than 6 months after completion of their last dose of platinum chemotherapy

For the last chemotherapy course immediately prior to randomisation on the study:

* Patients must be, in the opinion of the investigator, in response (partial or complete radiological response), or may have no evidence of disease (if optimal cytoreductive surgery was conducted prior to chemotherapy), and no evidence of a rising CA-125, following completion of this chemotherapy course
* Patient must have received a platinum based chemotherapy regimen (e.g. carboplatin or cisplatin) and have received at least 4 cycles of treatment
* Patients must be randomized within 8 weeks of their last dose of chemotherapy
* Maintenance treatment is allowed at the end of the penultimate platinum regimen, including bevacizumab

Exclusion Criteria:

* Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
* BRCA 1 and/or BRCA2 mutations that are considered to be non detrimental (e.g., "Variants of uncertain clinical significance" or "Variant of unknown significance" or "Variant, favor polymorphism" or "benign polymorphism" etc.)
* Patients who have had drainage of their ascites during the final 2 cycles of their last chemotherapy regimen prior to enrolment on the study.

Answer: A