Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised Phase II Study Of Nintedanib (BIBF1120) Compared To Chemotherapy in Patients With Recurrent Clear Cell Carcinoma Of The Ovary Or Endometrium
Brief Summary: The trial will recruit up to 120 patients; 90 with ovarian clear cell carcinoma and up to 30 with endometrial clear cell carcinoma. Patients will be randomised between chemotherapy and Nintedanib 200mg twice daily oral administration (PO) continuously. 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


Options:
A: Inclusion Criteria:

1. Women over 18 years old
2. Obtained informed consent, in writing and signed
3. Histological confirmation of primary peritoneal carcinoma or fallopian tube carcinoma
4. Planned interval debulking surgery
5. ECOG:0 to 2
6. Life expectancy \>12 weeks

Exclusion Criteria:

1. Non-epithelial ovarian cancer, including malignant mixed Müllerian tumors.
2. Borderline ovarian tumors.
3. Administration of intraperitoneal chemotherapy planned.
4. Previous systemic anti-tumor treatment against ovarian cancer.
5. Intestinal obstruction or sub-occlusion, intestinal infiltration shown by CT scan or rectosigmoid infiltration in gynaecological examination.
6. Uncontrolled hypertension.
7. Any previous radiotherapy: abdomen or pelvis.
8. Major traumatic injuries in the 4 weeks prior to the first potential dose of bevacizumab.
9. History or clinical suspicion of brain metastases or spinal cord compression.
10. History or evidence of central nervous system (CNS) disorders, unless properly treated with standard medical treatment.
11. Cerebrovascular accident (CVA), transient ischemic attack (TIA) or subarachnoid haemorrhage (SAH) in the 6 months prior to randomization.
12. Fertile women of childbearing age who are not willing to use effective contraception during the study and at least 6 months after the study.
13. Women that are breastfeeding or pregnant.
14. Prior exposure to mouse CA-125 antibody.
15. Treatment with any other experimental product, or participation in another clinical trial within 30 days prior to inclusion.
16. Malignant tumors other than ovarian cancer within the 5 years prior to randomisation, with the exception of cervical carcinoma in situ treated correctly and/or basal-cell carcinoma.
17. Known hypersensitivity to bevacizumab or any of its excipients (including Cremophor).
18. Non-healing wound, active peptic ulcer or bone fracture. Patients with healing incised granulomas by secondary intention, with no evidence of fascial dehiscence or infection can be included, but they require three weeks of wound control.
19. History or evidence of bleeding or thrombotic diathesis
20. Current or recent continued use of aspirin \> 325 mg / day (within 10 days prior to randomization)
21. Current or recent use (within 10 days before the first cycle of treatment) of full doses of anticoagulants or thrombolytics administered orally or parenterally for therapeutic purposes (except for vascular permeability, in which case the INR should be kept below 1.5).
22. Clinically significant cardiovascular disease, including:

    * Myocardial infarction or unstable angina (≤ 6 months before randomization)
    * Congestive heart failure (CHF) class ≥ II of the NYHA (New York Heart Association)
    * Poorly controlled cardiac arrhythmia despite medication (may include patients with atrial fibrillation with controlled frequency)
    * Peripheral vascular disease ≥ grade 3 (i.e. symptomatic and interfering with activities or daily living \[ADL\] needing repair or review)
23. Pre-existing sensory or motor neuropathy, ≥ grade 2
24. Demonstration of any other neurological or metabolic dysfunction involving a reasonable suspicion of the existence of a disease or condition that contraindicates the use of an experimental drug, or that involves an increased risk to the patient of treatment-related complications
25. No medical or psychiatric illness that may impede the performance of a systemic or surgical treatment
26. Laboratory:

Inadequate bone marrow function:

* ANC: \<1.5 x 109/l
* platelet count \<100 x 109/l
* Hb \<9 g/dl. (Patients may be transfused)

Inadequate coagulation parameters: Activated partial thromboplastin time (APTT) \>1.5 x ULN or INR \>1.5

Inadequate liver function, defined as:

* Serum (total) bilirubin \>1.5 x the upper limit of normal (ULN) for the institution
* AST \& ALT \> 2.5 x ULN (\> 5 x ULN in patients with liver metastases) or alkaline phosphatase \> 2.5 x ULN (or \> 5 x ULN in case of liver metastases or \> 10 x ULN in case of bone metastases).

Inadequate renal function, defined as:

* Serum creatinine \>2.0 mg/dl or \>177 mol/l
* Urine dipstick for proteinuria \>2+
* Patients with 2+ proteinuria on baseline dipstick analysis should undergo a 24-hour urine collection and must demonstrate ≤1g of protein in their 24-hour urine collection
B: Inclusion Critera

1. Female ≥ 18 years of age
2. Histologically proven diagnosis of:

   a. Endometrial and other uterine cancers with tumors of all histologies i. Recurrent Stage I to II endometrial and other uterine cancers, after at least one prior line of standard therapy, requiring further treatment with platinum-based chemotherapy ii. Advanced Stage III to IV endometrial and other uterine cancers requiring treatment with platinum-based chemotherapy

   b. Ovarian Cancer: Platinum-sensitive or platinum-resistant recurrent or metastatic ovarian, fallopian, or primary peritoneal cancer treated with at least one prior line of platinum-based chemotherapy and requiring further treatment.(Part 1/Phase Ib, Part 2/Phase 2a)

   Platinum-sensitive is defined as cancer progression ≥ 6 months after platinum- based chemotherapy. Platinum-resistant is defined as cancer progression \< 6 months after platinum-based chemotherapy.

   Histologic cell types eligible are endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified.

   Phase III/Part 3:

(1) Platinum-resistant (progression within 6 months after last platinum-based chemotherapy) ovarian, fallopian, or primary peritoneal cancer that meets one of the following criteria: i. Subject has received at least two prior lines of systemic therapy including a bevacizumab-containing regimen as standard of care ii. Subject has received at least two prior lines of systemic therapy, has not received a prior bevacizumab-containing regimen and is not eligible for a bevacizumab containing regimen based on Investigator's assessment (2) Platinum-refractory (progression during first-line platinum-based chemotherapy) ovarian, fallopian, or primary peritoneal cancer after at least one prior line of systemic therapy (3) For groups 1-2 above: Subjects with positive deleterious or suspected deleterious, germline or somatic BRCA mutated status must have received a PARP inhibitor as a prior line of therapy.

c. Cervical cancer: recurrent or metastatic cervical cancer that is not amenable to curative treatment with surgery and/or radiation therapy after at least one prior line of standard therapy, requiring further treatment. Histologic cell types eligible are squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma

3. Have measureable disease defined by RECIST 1.1 confirmed by CT or MRI scan within 28 days of enrollment.

4. Life expectancy of ≥ 3 months at the time of enrollment.

5. Able to take orally administered study medication.

6. Have adequate baseline function and performance status within 28 days of enrollment:

1. Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3, platelets ≥ 100,000/mm3
2. Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN) or if creatinine is \> 1.5 x ULN, creatinine clearance must be \> 50 mL/min.
3. Hepatic function: bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN for subjects with Gilbert Syndrome; AST and ALT ≤ 3.0 × ULN.
4. Coagulation profile: international normalized ratio (INR) is ≤ 1.5 and an aPTT or PTT \< 1.2 x ULN
5. ECOG performance ≤ 2

   7. Women of child-bearing potential must agree to use contraceptive measures starting 1 week before C1D1 until 4 weeks after the last dose of study treatment and have a negative serum pregnancy test within 28 days of enrollment.

   8. Provide written informed consent and authorization permitting release of Protected Health Information.

   9. Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures.

Exclusion Criteria

1. Serious, non-healing wound, ulcer or bone fracture.
2. Major surgical procedure within 28 days or minor surgical procedure performed within 7 days prior to C1D1 (a major surgical procedure is defined as requiring general anesthesia).
3. (Intentionally left blank)
4. Active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
5. History or evidence upon physical examination of central nervous system (CNS) disease including primary brain tumor; seizures not controlled with standard medical therapy; and history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA), or subarachnoid hemorrhage within 6 months of enrollment.

   a. Subjects with metastatic CNS tumors may participate in this study if the subject is \> 28 days from therapy completion (including radiation and/or surgery), is clinically stable at the time of study enrollment, and is not receiving corticosteroid therapy.
6. Proteinuria on urinalysis within 28 days of enrollment. Subjects discovered to have a urine protein of 1+ on dipstick or ≥ 30 mg/dl at baseline should undergo a 24-hour urine collection and demonstrate \< 1000 mg protein per 24 hours or spot urine protein (mg/dL) to creatinine (mg/dL) ratio must be \<1.0 to allow participation in the study.
7. Clinically significant cardiovascular disease including uncontrolled hypertension; myocardial infarction or unstable angina within 6 months prior to enrollment; New York Heart Association (NYHA) Grade II or greater congestive heart failure (Appendix E); serious cardiac arrhythmia requiring medication; and Grade II or greater peripheral vascular disease.
8. Women who are pregnant or nursing.
9. (Intentionally left blank)
10. Clinically significant, uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
11. Hemoptysis within 3 months prior to enrollment.
12. Acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction.
13. Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 28 days (42 days in cases of mitomycin C, nitrosourea, lomustine) prior to enrollment.
14. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 within 14 days prior to enrollment and during the study unless there is an emergent or life-threatening medical condition that required it.
15. Known history of human immunodeficiency virus infection (HIV).
16. Active bacterial infections requiring systemic antibiotics (excluding uncomplicated urinary tract infection).
17. Other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of other cancer present within the last 5 years prior to enrollment or whose previous cancer treatment contraindicates this protocol therapy.
18. History of non-malignant gastrointestinal bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3-months prior to enrollment that in the opinion of the investigator may place the subject at risk of side effects on an anti-angiogenesis product.
19. History of significant vascular disease (e.g. aortic aneurysm, aortic dissection).
20. Intra-abdominal abscess within the last 3 months of enrollment.
21. Pre-existing uncontrolled hypertension as documented by two baseline blood pressure readings taken at least five minutes apart, defined as systolic BP \>160 mm Hg or diastolic BP \> 90 mm Hg pressure.
22. QTc \> 470 msec on screening ECG per Fridericia's formula.
23. History of or existing risk factors for Torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
24. Concurrent use of concomitant medications that prolong the QT/QTc interval.
25. Baseline echocardiogram (within 56 days of enrollment) with left ventricular ejection fraction (LVEF) \< 50%.
26. History of difficulty swallowing, malabsorption, active partial or complete bowel obstruction, or other chronic gastrointestinal disease or condition that may hamper compliance and/or absorption of AL3818.
27. History of pancreatitis; history of renal disease that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy or other renal insufficiencies.
28. Treatment with an investigational agent within 28 days of enrollment.
29. Known recreational substance abuse.
30. Anticoagulation therapy with warfarin. Subjects treated with heparin, low molecular weight heparin, or any other anticoagulant may be included provided the subject has been on a stable therapeutic dose of the anticoagulant for at least 14 days prior to enrollment.
31. Known hypersensitivity to AL3818 or components of the formulation.
C: 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).
D: Inclusion Criteria:

1. Patients affected by pathologically confirmed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer.
2. Relapsed/progressive disease within 6 months from last platinum-based chemotherapy (platinum resistant/refractory disease).
3. Any line of treatment (after the first).
4. Any "last" chemotherapy line, including Paclitaxel, that should have been administered at least 6 months before the study beginning.
5. Patients must be women \> 18 years of age.
6. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:

   * Haemoglobin ≥ 10.0 g/dL and no blood transfusions in the 28 days prior to entry/randomization - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   * White blood cells (WBC) \> 3x109/L
   * Platelet count ≥ 100 x 109/L
   * Total bilirubin ≤ 1.5 x institutional Upper Limit of Normal (ULN)
   * AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional Upper Limit of Normal, unless liver metastases are present in which case it must be ≤ 5x ULN
   * Creatinine clearance estimated using the Cockcroft-Gault equation ≥51 mL/min,.
7. ECOG performance status 0-1.
8. Patients must have a life expectancy ≥ 16 weeks.
9. Evidence of non-childbearing status for women of childbearing potential (negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1 or postmenopausal women. Postmenopausal status is defined as:

   * Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
   * LH and FSH levels in the post-menopausal range for women under 50
   * Radiation-induced oophorectomy with last menses \>1 year ago,
   * Chemotherapy-induced menopause with \>1 year interval since last menses
   * Surgical sterilization (bilateral oophorectomy or hysterectomy)
10. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits and examinations including follow up.
11. At least one lesion (measurable as defined by RECIST 1.1) that can be accurately assessed by CT scan or MRI with Chest X-ray at baseline and follow up visits.
12. BRCA1-2 mutation status known. In case of BRCA status unknown, the BRCA test must be performed before the randomization or, if not feasible, within the end-of the study treatment.
13. Provision of informed consent prior to any study specific procedures. In case of patients unable to give written informed consent, is necessary to have the subject or legal representative sign, but in any case a witness must be present and sign and date with the person providing informed consent.

Exclusion Criteria:

1. Any previous treatment with a PARP inhibitor, including Olaparib.
2. Prior treatment with Cediranib (previous bevacizumab or other antiangiogenic drugs are allowed)
3. Previous progression to weekly Paclitaxel
4. Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≥ 5 years
5. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment with study drug.
6. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting Olaparib is 2 weeks.
7. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting Olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
8. Persistent toxicities (\>=CTCAE grade 2) with the exception of alopecia, caused by previous cancer therapy.
9. Resting ECG with QTc \> 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
10. Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart unless urinary protein \< 1.5g in a 24 hr period or urine protein/creatinine ratio \< 1.5.
11. A history of poorly controlled hypertension or resting blood pressure \>150/100 mmHg in the presence or absence of a stable regimen of anti-hypertensive therapy (measurements will be made after the patient has been resting supine for a minimum of 5 minutes. Two or more readings should be taken at 2-minute intervals and averaged. If the first two diastolic readings differ by more than 5 mmHg, then an additional reading should be obtained and averaged).
12. Blood transfusions within 28 days prior to study start.
13. Features suggestive of Myelodysplastic syndrome or Acute myeloid leukemia (MDS/AML) on peripheral blood smear.
14. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment.
15. Major surgery within 4 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
16. Patients considered at poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent.
17. Patients unable to swallow medications and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
18. Breast feeding women.
19. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy.
20. Patients with known active hepatic disease (i.e., Hepatitis B or C).
21. Patients with a known hypersensitivity to Olaparib, Cediranib or any of the excipients of the products.
22. Patients with a known hypersensitivity to Paclitaxel.
23. Patients with uncontrolled seizures.
24. History of abdominal fistula or gastrointestinal perforation.
25. Prior gastrectomy.

Answer: C