Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II, Open-Label, Randomised, Comparative, International Multicentre Study to Assess the Safety and Efficacy of Different Doses of AZD2281 Given Orally Twice Daily Versus Intravenous Liposomal Doxorubicin Given Monthly in Patients With Advanced BRCA1- or BRCA2-Associated Ovarian Cancer Who Have Failed Previous Platinum-based Chemotherapy
Brief Summary: The purpose of the study is to compare the efficacy and safety of 2 doses of drug AZD2281 against liposomal doxorubicin to see which is effective and well tolerated in treating patients with measurable BRCA1- or BRCA2-positive advanced ovarian cancer and who have failed previous platinum therapy.


Options:
A: Inclusion Criteria:

1. Progressive or recurrent ovarian peritoneal or fallopian tube clear cell carcinoma, or progressive or recurrent endometrial clear cell carcinoma. The primary diagnosis must be histologically confirmed and central pathological review of the presenting tumour or biopsy of relapsed disease must find at least 50% clear cell carcinoma with no serous differentiation. Progressive disease as defined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1.
2. Failure after ≥1 prior platinum containing regimen which may have been given in the adjuvant setting. For patients with ovarian clear cell carcinoma, progression must have occurred within 6 calendar months of their last platinum dose.
3. ECOG (Eastern Cooperative Oncology Group) Performance status of ≤2.
4. Life expectancy of \>3 months.
5. Adequate hepatic, bone marrow coagulation and renal function

   1. Hepatic function: total bilirubin \< Upper Limit of Normal (ULN); ALT and AST \< 2.5 x ULN
   2. Coagulation parameters: INR (International Normalised Ratio) \<2 x ULN and prothrombin time and activated partial thromboplastin time \< 1.5 x ULN in the absence of therapeutic anticoagulation
   3. absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   4. platelets ≥ 100 x 109L
   5. haemoglobin ≥ 9.0 g/dL
   6. proteinuria \< grade 2 CTCAE (version 4)
   7. Glomerular Filtration Rate ≥40ml/min. (calculated using the Wright, Cockroft \& Gault equation or measured by EDTA clearance)
6. Female and \> 18 years of age.
7. Signed and dated written informed consent prior to admission to the study in accordance with International Conference on Harmonization on Good Clinical Practice (ICH-GCP) guidelines and local legislation.
8. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures.

Exclusion Criteria:

1. Prior treatment with Nintedanib or other angiogenesis inhibitor/VEGF targeted therapy, except for prior treatment with bevacizumab which is permitted.
2. Treatment within 28 days prior to randomisation with any investigational drug, radiotherapy, immunotherapy, chemotherapy, hormonal therapy or biological therapy. Palliative radiotherapy may be permitted for symptomatic control of pain from bone metastases in extremities, provided that the radiotherapy does not affect target lesions, and the reason for the radiotherapy does not reflect progressive disease.
3. Previous treatment with the chemotherapy regimen selected as the control arm by the investigator. (Prior therapy with paclitaxel given on a three weekly regimen is permitted for patients receiving weekly paclitaxel. Prior treatment with weekly paclitaxel is permitted where this has been used as part of first line therapy and it is greater than 6 months since the last dose of weekly paclitaxel. Prior weekly paclitaxel for relapsed disease is not permitted).
4. Other malignancy diagnosed within 5 years of enrolment except for:

   1. non-melanomatous skin cancer (if adequately treated)
   2. cervical carcinoma in situ (if adequately treated)
   3. carcinoma in situ of the breast (if adequately treated)
   4. For patients with ovarian clear cell cancer, prior or synchronous endometrial cancer (if adequately treated), provided all of the following criteria are met:

      * disease stage FIGO (International Federation of Gynecology and Obstetrics) Stage 1a (tumour invades less than one half of myometrium)
      * Grade 1 or 2
5. Patients with any other severe concurrent disease, which may increase the risk associated with study participation or study drug administration and, in the judgement of the investigator, would make the patient inappropriate for entry into this study, including significant neurologic, psychiatric, infectious, hepatic, renal, or gastrointestinal diseases or laboratory abnormality.
6. Symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other gastro-intestinal disorders or abnormalities, including difficulty swallowing, that would interfere with drug absorption.
7. Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy, including known hepatitis B and/or C infection and HIV-infection.
8. Symptomatic central nervous system (CNS) metastasis or leptomeningeal carcinomatosis.
9. Known, uncontrolled hypersensitivity to the investigational drugs or their excipients.
10. Hypersensitivity to Nintedanib, peanut or soya, or to any of the excipients of Nintedanib.
11. Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within 6 months prior to randomisation, congestive heart failure \> NYHA (New York Heart Association) III, severe peripheral vascular disease, clinically significant pericardial effusion.
12. History of major thromboembolic event, such as pulmonary embolism or proximal deep vein thrombosis, unless on stable therapeutic anticoagulation
13. Known inherited predisposition to bleeding or thrombosis.
14. History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 6 months.
15. History of clinically significant haemorrhage in the past 6 months.
16. Major injuries or surgery within the past 28 days prior to start of study treatment or planned surgery during the on-treatment study period.
17. Pregnancy or breastfeeding. Patients with preserved reproductive capacity must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment.
18. Patients with preserved reproductive capacity, unwilling to use a medically acceptable method of contraception (see section 5.7) for the duration of the trial and for 6 months afterwards.
19. Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels.
20. Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the study protocol and follow up schedule; those considerations should be discussed with the patient before registration in the trial.
21. Patients who have already received maximal lifetime dose of anthracycline or have experienced cardiac toxicity from an anthracycline should not receive doxorubicin or Paclitaxel Liposomal Doxorubicin (PLD).
B: Inclusion Criteria:

* Women, 18 years and older, written (signed and dated) informed consent
* Histological confirmed epithelial ovarian cancer, primary cancer of the peritoneum or fallopian tube
* Up to three prior chemotherapies, at least one platinum based chemotherapy
* Platinum refractory or resistant ovarian cancer (defined as stable (SD) or progressive disease (PD) during platinum containing chemotherapy, or treatment free interval \< 6 months after stop of platinum based chemotherapy)
* Measurable or non-measurable disease
* Elevated CA°125 level (\> 2 x ULN in case of normal CA°125 after prior chemotherapy; or ≥ 2 x nadir CA°125 value after prior chemotherapy, when CA° 125 levels remained elevated above normal) in case of non-measurable disease
* ECOG performance status 0-2
* Negative pregnancy test within 5 days before randomization and adequate contraception in women with childbearing potential

Adequate organ function as defined by the following criteria:

* Serum aspartate aminotransferase (AST; serum glutamate-oxalate transferase \[SGOT\]) and serum alanine aminotransferase (ALT; serum glutamate-pyruvate transferase \[SGPT\]) \<=2.5 x upper limit of normal (ULN). If liver function abnormalities are due to underlying malignancy, then AST and ALT may be \<=5x ULN
* Total serum bilirubin \<=1.5 x ULN
* Prothrombin time (PT) and partial thromboplastin time (PTT) \<=1.5 x ULN
* Serum albumin \>= 3.0 g/dL
* Absolute neutrophil count (ANC) \>=1500/µl
* Platelets \>=100,000/µl
* Hemoglobin \>=9.0 g/dL
* Serum creatinine \<=1.5 x ULN
* TSH within normal range Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures Resolution of all toxic effects of any prior chemotherapy, surgical procedures, radiotherapy, or other cancer related therapies to NCI CTCAE (Version 3.0) grade \>=1 and to the baseline laboratory values as defined in inclusion criterion (see before)

Exclusion Criteria:

* Borderline tumor of the ovaries
* Acute or chronic infection
* Any required concurrent cancer chemotherapy or antineoplastic endocrine therapy or radiotherapy
* Exposure to investigational trial medication, cancer chemo- or radiotherapy within the last 28 days prior to start of study treatment
* Known or suspected hypersensitivity to investigational compound
* Second malignancy interfering with prognosis of the patient
* Cachectic patients with a body weight \<45 kg
* Patients requiring parenteral nutrition
* Patients with ileus within the last 28 days
* Any of the following within the 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other thromboembolic event
* Current treatment with therapeutic doses of anticoagulant
* Current treatment with CYP3A4 inhibitors or -inducers
* Hypertension that cannot be controlled by medications (\>150/100 mmHg despite optimal medical therapy)
* Ongoing cardiac dysrhythmias of NCI CTCAE grade \>=2, atrial fibrillation of any grade, or prolongation of the QTc interval to \>470 msec for females

  * Left ventricular ejection fraction (LVEF) \<=50% as measured by echocardiogram
  * NCI CTCAE Grade 3 hemorrhage within 4 weeks of starting study treatment
* Evidence of neurological signs/symptoms suggestive of brain metastases, spinal cord compression, or new evidence of brain or leptomeningeal disease
* Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS)-related illness
* Patients with any other severe concurrent disease, which is an undue risk for the patient by participating in the present study
* Any further condition which according to the investigator results in an undue risk of the patient by participating in the present study
* Major surgery, radiation therapy, or systemic therapy within 3 weeks of first study treatment. At least 7 days should elapse from the time of minor surgical procedure including placement of an access device or fine needle aspiration before randomization into this study can occur.
* Wounds that have not completely healed, active ulcer(s), or bone fracture(s).
* Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.
* Prior radiation therapy to \>25% of the bone marrow.
C: Inclusion Criteria:

* First diagnosis of histological confirmed (cytology alone excluded) epithelial ovarian cancer, fallopian tube or primary peritoneal cancer. Histology should be obtained by laparoscopy (or by laparotomy),
* FIGO-Stages IIIC - IV,
* ECOG performance status \< 2,
* Life expectancy of at least 6 months,
* Primary debulking surgery denied and maximum surgical effort of cytoreduction with the goal of no residual disease planned as interval debulking surgery,
* Interval between diagnosis and enrolment (informed consent) ≤ 8 weeks,
* Adequate hepatic, renal and bone marrow functions:

Platelets \> 100 000 /μL, Hemoglobin \> 9.0 g/dL, Absolute Neutrophil Count (ANC) \> 1500/μL, Prothrombin time and/or partial thromboplastin time \< 50% deviation from normal limits in the absence of therapeutic anticoagulation, Proteinuria \< CTCAE grade 2, Total bilirubin ≤ upper limit of normal (ULN), ALT and/or AST ≤ 2.5 x ULN, Glomerular filtration rate \>40 mL/min,

* Females, age 18 years or older,
* Patient has given written informed consent,

Exclusion Criteria:

* Histological diagnosis of malignant tumour of non-epithelial origin (e.g. germ cell tumour, malignant mixed mullerian tumour, sex cord-stromal tumour) of the ovary, the fallopian tube or peritoneum or borderline tumour of the ovary (tumour of low malignant potential),
* Non-healing wound, ulcer (intestinal tract, skin) or bone fracture,
* Clinical symptoms or signs of gastrointestinal obstruction,
* History of major thromboembolic event, defined as:

  * Pulmonary embolism (PE) within 6 months prior to enrolment,
  * Recurrent pulmonary embolism (history of at least 2 events),
* History of at least 2 unprovoked (without a transient or reversible risk factor) events of proximal deep venous thrombosis,
* Prior thrombosis or thromboembolic event in the presence of an inherited coagulopathy (including deficiency of antithrombin, deficiency of protein C or protein S, Factor V Leiden mutation, Prothrombin G20210A mutation),
* Patients with perioperative thrombosis including proximal deep vein thrombosis (DVT) or thrombosis of visceral vessels not associated with pulmonary embolism may be included in the trial if stable therapeutic anticoagulation is documented,
* Known inherited or acquired bleeding disorder,
* Significant cardiovascular diseases, including:

  * Hypertension not controlled by medical therapy,
  * Unstable angina within the past 6 months,
  * History of myocardial infarction within the past 6 months,
  * Congestive heart failure \> NYHA II,
  * Clinically relevant cardiac arrhythmia
* Peripheral vascular disease Fontaine stage ≥3,
* Clinically relevant pericardial effusion (e.g. pericardial effusion with echocardiographic or clinical signs of haemodynamic impairment),
* History of a cerebral vascular accident, transient ischemic attack or subarachnoid hemorrhage within the past 6 months,
* Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy, including HIV-infection, hepatitis B and/or C infection,
* Poorly controlled diabetes mellitus or other contraindication to high dose corticosteroid therapy,
* Clinical symptoms of brain metastases and/or diagnosis of brain metastases on imaging,
* Pre-existing sensory or motor neuropathy CTCAE ≥ 2, except due to trauma,
* Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug,
* Other malignancy diagnosed within the past 5 years, except:

  * non-melanomatous skin cancer (if adequately treated),
  * cervical carcinoma in situ (if adequately treated),
  * carcinoma in situ of the breast (if adequately treated),
  * prior or synchronous endometrial cancer (if adequately treated), provided the following criteria are met:

    * Disease stage FIGO ≤ IB,
    * No more than superficial myometrial invasion,
    * Not poorly differentiated (less than grade 3, no papillary serous or clear cell histology),
* Prior systemic therapy for ovarian cancer (e.g. chemotherapy, monoclonal antibody therapy, oral targeted therapy, hormonal therapy),
* Prior radiotherapy to the abdomen or prior radiotherapy to an extra-abdominal target volume that would bear the risk of increased toxicity of chemotherapy,
* Hypersensitivity to Vargatef® (Nintedanib) and/or the excipients of the trial drugs,
* Serious illness or concomitant non-oncological disease such as neurologic, psychiatric or infectious disease, active ulcers (gastrointestinal tract, skin) or a laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study,
* Patients with preserved reproductive capacity who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner) during the trial and for at least twelve months after end of active therapy,
* Pregnancy or breast feeding,
* Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule,
* Active alcohol or drug abuse,
* Any contraindications for therapy with paclitaxel or carboplatin, e.g. a history of severe hypersensitivity reactions to paclitaxel or platinum-containing compounds and their excipients, or other drugs formulated with Polyoxyl 35 Castor Oil - ELP,
* Treatment with other investigational drugs or participation in another clinical trial testing a drug within the past four weeks before start of therapy or concomitantly with this trial.
D: Inclusion Criteria:

* Advanced ovarian cancer with positive BRCA1 or BRCA2 status
* Progressive or recurrent disease after platinum-based chemotherapy
* Measurable disease by RECIST

Exclusion Criteria:

* Previous anthracycline treatment
* Brain metastases
* Less than 28 days since last treatment used to treat the disease
* Considered a poor medical risk due to a serious uncontrolled disorder

Answer: D