Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 1 Study Evaluating the Safety, Pharmacokinetics and Pharmacodynamics of AMG 386 in Adult Patients With Advanced Solid Tumors
Brief Summary: The purpose of this study is to test the safety, tolerability and pharmacokinetic (PK) profile of AMG 386 after intravenous administration in adult subjects with advanced solid tumors.


Options:
A: Inclusion Criteria:

* Female subjects, ≥18 years, histologically proven recurrent advanced epithelial ovarian, fallopian tube or primary peritoneal carcinomas
* Have either undergone a hysterectomy or bilateral oophorectomy/salpingectomy and/or have been postmenopausal for 24 consecutive months (i.e. who have not had menses at any time in the preceding 24 consecutive months without an alternative medical cause)
* Performance status 0-2
* Adequate organ function
* Life expectancy \>6 weeks
* Has received 2 or more lines of chemotherapy for ovarian cancer and patient is platinum resistant or platinum intolerant or not suitable for any further standard intravenous chemotherapy
* No previous oral cyclophosphamide, nintedanib, or other tyrosine kinase inhibitors such as cediranib but patients can have received anti-VEGF therapies such as bevacizumab as they will be stratified for this
* Measurable lesions according to RECIST 1.1 criteria or serum CA125 levels for evaluation by GCIG CA125 criteria are welcomed but not a prerequisite for inclusion as response will only be assessed for those with evaluable disease
* Able to give written informed consent and to complete QoL

Exclusion Criteria

* Carcinosarcoma or malignant tumour of non-epithelial origin (e.g. germ cell tumour, sex cord-stromal tumour) of the ovary, fallopian tube or peritoneum
* Clinically relevant non-healing wound, ulcer (intestinal tract, skin) or bone fracture
* Symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other GI disorders or abnormalities that would interfere with drug absorption or inability to take oral medication
* Active brain metastases (i.e. symptoms deteriorating, changing condition in \< 4 weeks) or leptomeningeal disease. Trial entry is allowed if the brain metastases are stable (asymptomatic or condition stable for \> 4 weeks).
* Dexamethasone for brain metastases is allowed if administered as stable dose for \> 4 weeks before randomisation (if \< 4 weeks then the patient is not eligible)
* Clinically relevant therapy-related toxicity from previous chemotherapy and radiotherapy
* History of major thromboembolic event within the last 6 months, such as pulmonary embolism or proximal deep vein thrombosis, unless on stable therapeutic anticoagulation (\>3 months if on warfarin, PT / INR needs to be monitored regularly as per table 8.1 in protocol)
* Known inherited or acquired bleeding disorder
* Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within the past 6 months, congestive heart failure \> NYHA II, severe peripheral vascular disease, significantly relevant pericardial effusion
* History of a cerebral vascular accident, transient ischemic attack or subarachnoid hemorrhage within the past 6 months
* Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels
* Laboratory values indicating an increased risk for adverse events:

  1. calculated GFR \< 45 ml/min. Sites can use any calculation method according to local practice.
  2. absolute neutrophil count (ANC) \< 1.5x109/L
  3. platelets \< 100 x109/L
  4. haemoglobin \< 90 g/L
  5. proteinuria CTCAE 2 or greater
  6. total bilirubin \> x 2 ULN
  7. ALT and/or AST \> 1.5 x ULN
  8. unless liver metastases present when ALT or AST \> 2.5 ULN
  9. International normalized ratio (INR) \> 2 or activated partial thromboplastin time (APTT) \>1.5 x ULN in the absence of therapeutic anticoagulation. INR \> 4 or APTT \> 2.5 x ULN in presence of therapeutic anticoagulation
* Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal or antiviral therapy), including hepatitis B and/or C infection, HIV- infection
* Poorly controlled diabetes mellitus or patient on sulphonylurea-type hypoglycaemics (e.g. gliclazide) as main diabetic control (as contraindicated with cyclophosphamide)
* Previous breast cancer patients are permitted only if diagnosis and any chemotherapy treatment for this was \> 5 years previously and there is no evidence of metastatic breast cancer at trial entry (Please contact UCL CTC / CI if patient still on hormone treatment for breast cancer).
* Other malignancy diagnosed within the past 5 years. In exception to this rule, the following malignancies may be included:

  1. non-melanoma skin cancer (if adequately treated)
  2. cervical carcinoma in situ (if adequately treated)
  3. prior or synchronous endometrial cancer (if adequately treated), provided all of the following criteria are met: G1 or G2, no LVSI and FIGO (2010) stage IA only
* Serious illness or concomitant non-oncological disease such as neurologic, psychiatric or infectious disease 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
* Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule e.g. active alcohol or drug abuse
* Any contraindications for therapy with cyclophosphamide, e.g. a history of severe hypersensitivity reactions to listed excipients for cyclophosphamide treatment with other investigational drugs
* Patients should not commence trial treatment within 6 weeks of any major surgical procedure
* Participation in another clinical trial testing a drug within the past four weeks before start of therapy or concomitantly with this trial
* Chemotherapy, including immunotherapy or monoclonal antibody treatment (VEGF) within 4 weeks of starting study treatment
* Hormone treatment for ovarian cancer within 2 weeks of starting study treatment (ongoing HRT is allowable)
* Any previous tyrosine kinase inhibitor treatment that has predominantly anti-angiogenic action
* Radiotherapy within 3 months not allowed except when given for symptom control \>28d previously. All patients receiving any radiotherapy will require evidence of recurrent ovarian cancer outside the irradiated field either on imaging or via rising CA125
* Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients of nintedanib
B: Inclusion Criteria:

* Cytologic / histologic diagnosis of stage IC-IV ovarian cancer
* Disease progressed during first line chemotherapy or disease relapsed within 6 months after the last platinum treatment
* Disease evaluable by RECIST or Ca 125 GCIG criteria
* No residual peripheral neurotoxicity from previous chemotherapy treatment
* PS 0-1
* Aged at least 18 and not greater than 75 years.
* Life expectancy of at least 3 months
* Able to swallow and retain oral medication
* Written informed consent prior to performance of study specific procedures or assessments
* Ability and willingness to comply with treatment and follow up assessments and procedures

Exclusion Criteria:

· • Previous or concomitant malignant neoplasia (not including basocellular or spinocellular skin carcinoma or in-situ carcinoma of the uterine cervix, provided they are being adequately treated)

* Previous treatment with weekly paclitaxel
* More than 2 previous chemotherapy treatments
* Serious heart disease, including heart failure, atrioventricular block of any degree, serious arrhythmia or history of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina, symptomatic peripheral vascular disease, coronary artery by-pass graft surgery, class II, III or IV congestive heart failure as defined by the New York Heart Association (NYHA)
* Hemoglobin \< 9 g/dL, neutrophils \< 1500/mm3, platelets \< 100000/mm3
* Impairment of renal function (patients should have 2 functioning kidneys): creatinine 1.5 times the upper normal limit - UNL; calculated creatinine clearance \< 50 mL/min; urine protein to creatinine ratio \> or = 1: then, a 24-hour urine protein must be assessed and subject must have a 24-hour urine protein value \<1gr to be eligible
* Impairment of liver function (SGOT or SGPT \> or = 2.5 UNL, alkaline phosphatase \> 2.5 ULN, total bilirubin \> 1.5 times the UNL)
* Prothrombin time (PT) or international normalized ratio (INR) or activated partial thromboplastin time (PTT) \> 1.2 times the UNL
* Pregnancy, breast feeding, or inadequate contraception
* Unable to discontinue prohibited medications (see protocol section 6.7)
* Clinically significant gastrointestinal abnormalities which might interfere with oral dosing, including but not limited to malabsorption syndrome, major resection of the stomach or small bowel that could affect drug absorption, active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, other gastrointestinal conditions with increased risk of perforation, history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment, signs or symptoms of GI obstruction
* Any unstable or serious concurrent condition
* Prolongation of corrected QT interval (QTc) \>480 ms
* History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months
* Macroscopic hematuria
* Major surgery or trauma within 30 days
* Hypertension uncontrolled with adequate therapy (systolic blood pressure (BP) of \> or = 140mmHg, or diastolic BP of \> or = 90mmHg)
* Any ongoing toxicity from prior anti-cancer therapy that is \>Grade 1 and/or that is progressing in severity
* Present or suspected haemorrhagic syndromes
* Patients' inability to access the centre due to area of residence
C: Participants that met the following criteria were eligible.

Inclusion Criteria:

* Symptomatic malignant ascites resulting from advanced ovarian epithelial cancer (including fallopian tube and primary peritoneal adenocarcinoma) that required at least 3 previous therapeutic paracenteses at a frequency of 1 to 4 paracenteses per month for management.
* Platinum resistant disease defined by relapse or progression of disease during or after treatment, or drug intolerance.
* Topotecan- and/or liposomal doxorubicin-resistant disease defined by relapse or progression of disease during or after treatment, or drug intolerance.

Exclusion Criteria:

* Peritoneovenous or other type of shunt that was placed for the management of ascites
* Prior treatment with a VEGF or VEGF receptor inhibitor
* Uncontrolled hypertension

The above information is not intended to contain all considerations relevant to participation in a clinical trial.
D: Inclusion Criteria: - Have evaluable disease - Must be able to undergo MRI evaluation:

1. Must not have cardiac pacemakers or neurostimulators not specifically approved for use in the MRI environment;
2. Must not have metal implants, other than those approved as safe for use in MRI;
3. Must not be claustrophobic or have physical characteristics that will preclude undergoing MRI; - Subjects enrolling to the Dose Expansion Cohort must have at least one tumor that is amenable to DCE-MRI evaluation (e.g., greater than or equal to 3 cm lesion outside the thoracic cavity) - Have Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2 - Adequate hematologic, renal and hepatic function Exclusion Criteria: - Presence of untreated CNS metastasis or symptoms of brain metastases - Presence of leukemia or myelodysplastic syndrome - History of high-dose chemotherapy requiring bone marrow or peripheral stem cell support - Unstable or uncontrolled disease or condition related to or impacting cardiac function (e.g., unstable angina, congestive heart failure \[NYHA greater than class II\], uncontrolled hypertension \[diastolic greater than 85 mmHg; systolic greater than 145 mmHg\] or cardiac arrhythmia) - History of arterial thrombosis (i.e., stroke, transient ischemic attack or myocardial infarction) within 6 months of study day 1 - History of bleeding diathesis or hypercoagulopathy within 6 months of study day 1 - Active peptic ulcer disease or gastritis - Unresolved toxicities from prior anti-cancer therapy, excluding alopecia - Anti-tumor treatment within 3 weeks of study day 1. If anti-tumor treatment was an antibody therapy, the interval must be 6 weeks - Anticoagulation therapy, except a low dose of Coumadin™ (less than 2 mg) for prophylaxis against central catheter-related thrombosis - Major surgery within 4 weeks of study day 1 - History of allergic reaction to bacterially produced proteins - Known positive test for human immunodeficiency virus (HIV) infection, hepatitis C virus or chronic hepatitis B infection - Pregnant or breastfeeding - Not using adequate contraceptive precautions, in the judgment of the investigator

Answer: D