Please select the eligibility criteria that correspond to the clinical trial below.
Title: Phase II, Randomised, Placebo Controlled, Multicentre, Feasibility Study of Low Dose (Metronomic) Cyclophosphamide With and Without Nintedanib (BIBF 1120) in Advanced Ovarian Cancer
Brief Summary: The primary objective is to explore the efficacy and safety of an all oral combination of BIBF 1120 (an inhibitor of angiogenic signalling) and metronomic cyclophosphamide in patients with multiply-relapsed advanced ovarian cancer, who have completed a minimum of two lines of previous chemotherapy and who for any reason are not suitable for further 'standard' intravenous chemotherapy treatments.


Options:
A: Inclusion Criteria:

* written informed consent
* At least 18 years old.
* Histologically confirmed, International Federation of Gynecology and Obstetrics (FIGO) stage II-IV epithelial ovarian, fallopian tube or primary peritoneal carcinoma that was treated with surgical debulking and at least five cycles of platinum-taxane doublet chemotherapy.
* Study randomization at least 3 weeks and not more than 12 weeks from the date of the last chemotherapy dose, and all major toxicities from the previous chemotherapy must have resolved.
* No evidence of disease progression
* Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2
* Able to swallow and retain oral medication.
* Adequate hematologic, hepatic, and renal system function as follows:

Hematologic

* Absolute neutrophil count (ANC) at least 1.5 X 10\^9/L
* Hemoglobin at least 9 g/dL (or 5.59 mmol/L)
* Platelets at least 100 X 10\^9/L
* Prothrombin time (PT) or international normalized ratio (INR) up to 1.2 X ULN
* Activated partial thromboplastin time (aPTT) up to 1.2 X ULN Hepatic
* Total bilirubin up to 1.5 X ULN
* AST and ALT up to 2.5 X ULN Renal
* Serum creatinine up to 1.5 mg/dL

Or, if greater than 1.5 mg/dL:

Calculated creatinine clearance at least 50 mL/min Urine Protein

* Urine protein is 0, trace, or +1 determined by dipstick urinalysis, or \< 1.0 gram determined by 24-hour urine protein analysis.
* Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) OR childbearing potential, and agrees to use adequate contraception.

Exclusion Criteria:

* Either (a) bulky disease, or (b) any residual disease which in the opinion of the investigator will need imminent second-line therapy
* Synchronous primary endometrial carcinoma, or a past history of primary endometrial carcinoma, are excluded unless certain conditions are met.
* Clinically significant gastrointestinal abnormalities
* Prolongation of corrected QT interval (QTc) \> 480 msecs
* History of any one or more cardiovascular conditions within the past 6 months prior to randomization
* Poorly controlled hypertension
* History of cerebrovascular accident (including transient ischemic attacks), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months prior to randomization
* Major surgery (including interval debulking) or trauma within 28 days, or minor surgical procedures within 7 days, prior to randomization, or has any non-healing wound, fracture, or ulcer.
* Evidence of active bleeding or bleeding diathesis.
* Hemoptysis within 6 weeks prior to randomization.
* Endobronchial metastases.
* Serious and/or unstable pre-existing medical (e.g., uncontrolled infection), psychiatric, or other condition that could interfere with subject's safety, provision of informed consent, or compliance to study procedures.
* Investigational or anti-VEGF anticancer therapy prior to study randomization.
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib.
* Prior or concurrent invasive malignancies that currently or within the last 5 years show/ed activity of disease (except ovarian, fallopian tube, or peritoneal cancer, or concurrent endometrial cancer FIGO stages IA/B)
B: Inclusion Criteria:

* The subject has a cytologically or histologically and radiologically confirmed, advanced, recurrent, or metastatic solid tumor of the nine types listed below:

  * Pancreatic Cancer
  * Castration-Resistant Prostate Cancer (CRPC)
  * Hepatocellular Carcinoma (HCC)
  * Gastric or Gastroesophageal Junction Cancer
  * Melanoma
  * Small Cell Lung Cancer (SCLC)
  * Ovarian cancer, primary peritoneal or fallopian tube carcinoma
  * Breast cancer that is one of the following subtypes: estrogen receptor positive breast cancer, estrogen receptor/progesterone receptor/HER2-negative (triple-negative), or inflammatory (regardless of receptor status) disease histology
  * Non-Small Cell Lung Cancer (NSCLC)
* Certain requirements for prior therapies may apply
* The subject has documented progressive disease at screening
* Subjects having any tumor type of other than CRPC must have at least one lesion that is not within a previously irradiated field and is measurable on CT or MRI scan
* The subject has recovered to baseline or CTCAE ≤ Grade 1 from toxicities related to prior treatment (some exceptions apply)
* The subject is ≥ 18 years old on the day of consent
* Tissue samples from archival or fresh tissue, or a tissue block of the subject's tumor
* The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* The subject has adequate organ function
* The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document
* Sexually active fertile subjects (male and female), and their partners, must agree to use medically accepted methods of contraception during the course of the study and for 3 months after the last dose of the study drug(s)
* Female subjects of childbearing potential must have a negative pregnancy test at screening

Exclusion Criteria:

* The subject has experienced clinically-significant hematemesis or hemoptysis of \>0.5 teaspoon of red blood, or other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
* The subject has a cavitating pulmonary lesion(s) or a pulmonary lesion abutting or encasing a major blood vessel
* Certain restrictions on prior treatments apply
* The subject has known symptomatic or uncontrolled brain metastases or epidural disease
* The subject has prothrombin time/International Normalized Ratio (PT/INR) or partial thromboplastin time (PTT) test results that are above (1.3x)the laboratory upper limit of normal
* The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or Coumadin-related agents, heparin, thrombin or FXa inhibitors, and antiplatelet agents (low-dose aspirin (≤81 mg/day), low-dose warfarin (≤1mg/day, and prophylactic low molecular weight heparin (LMWH) are permitted)
* The subject has a corrected QT interval(QTcF)\>500 ms at screening
* The subject has uncontrolled, significant intercurrent illness
* The subject is unable to swallow capsules
* The subject is pregnant or breastfeeding
* The subject has a previously-identified allergy or hypersensitivity to components of the study treatment formulation
* The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee
* The subject has had another diagnosis of malignancy requiring systemic treatment within the last two years, unless non-melanoma skin cancer, in-situ carcinoma of the cervix, or superficial bladder cancer
C: 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
D: Inclusion Criteria:

* Patients must have recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma; histologic documentation of the original primary tumor is required via the pathology report
* Patients must have measurable disease or non-measurable (detectable) disease:

  * Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be greater than or equal to 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or greater than or equal to 20 mm when measured by chest x-ray; lymph nodes must be greater than or equal to 15 mm in short axis when measured by CT or MRI
  * Non-measurable (detectable) disease is defined in this protocol as the absence of measurable disease but at least one of the following conditions:

    * Ascites and/or pleural effusion attributed to tumor
    * Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions
* Patients with measurable disease must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
* Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG) protocol, if one exists; in general, this would refer to any active GOG phase III or rare tumor protocol for the same patient population; in addition, patients must not be eligible for the currently active phase II cytotoxic protocol in platinum resistant disease
* Patients must have a GOG performance status of 0, 1, or 2
* Recovery from effects of recent surgery, radiotherapy, or chemotherapy to baseline or CTCAE =\< grade 1 toxicity from all prior therapies except alopecia and other non-clinically significant adverse events (AE's):

  * Patients should be free of active infection requiring antibiotics (with the exception of uncomplicated urinary tract infection \[UTI\])
  * Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to treatment
  * Any other prior therapy directed at the malignant tumor, including chemotherapy, biological/targeted (non-cytotoxic) agents and immunologic agents, must be discontinued at least three weeks prior to treatment
  * Chimeric or human or humanized monoclonal antibodies (including bevacizumab) or vascular endothelial growth factor (VEGF) receptor fusion proteins (including VEGF TRAP/aflibercept) must be discontinued for at least 12 weeks prior to treatment
  * Investigational agents must be discontinued for at least 28 days prior to treatment
  * Any prior radiation therapy must be discontinued at least four weeks prior to treatment
* Prior therapy

  * Patients must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound; this initial treatment may have included intraperitoneal therapy, consolidation, biologic/targeted (non-cytotoxic) agents (e.g., bevacizumab) or extended therapy administered after surgical or non-surgical assessment; if patients were treated with paclitaxel for their primary disease, this could have been given weekly or every 3 weeks
  * Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum, non-taxane regimen; treatment with weekly paclitaxel for recurrent or persistent disease is NOT allowed
  * Patients are allowed to receive, but are not required to receive, biologic/targeted (non-cytotoxic) therapy as part of their primary treatment regimen
  * Patients must have NOT received any biologic/targeted (non-cytotoxic) therapy targeting the VEGF and/or MET pathways for management of recurrent or persistent disease
  * For the purposes of this study, poly (adenosine diphosphate \[ADP\]-ribose) polymerase (PARP) inhibitors will be considered "cytotoxic"; patients are allowed to receive, but are not required to receive, PARP inhibitors for management of primary or recurrent/persistent disease (either alone or in combination with cytotoxic chemotherapy); PARP inhibitors will NOT count as a prior regimen when given alone
* Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl
* Platelets greater than or equal to 100,000/mcl
* Hemoglobin greater than or equal to 9 g/dL
* Prothrombin time (PT) such that international normalized ratio (INR) is less than or equal to 1.3 x institutional upper limit of normal (ULN)
* Partial thromboplastin time (PTT) less than or equal to 1.3 x ULN
* Creatinine less than or equal to 1.5 x ULN
* Phosphorus, corrected calcium, magnesium and potassium greater than or equal to institutional lower limit of normal (LLN)
* Urine protein creatinine (UPC) ratio must be \< 1.0 gm; if UPC ratio \>= 1, collection of 24-hour urine measurement of urine protein is recommended
* Bilirubin less than or equal to 1.5 x ULN
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x ULN
* Alkaline phosphatase less than or equal to 2.5 x ULN
* Albumin greater than or equal to 2.8 g/dL
* Lipase less than or equal to 2 x ULN
* No radiologic or clinical evidence of pancreatitis
* Patients must have a normal baseline thyroid stimulating hormone (TSH); a history of hypothyroidism and/or hyperthyroidism is allowed
* Neuropathy (sensory and motor) less than or equal to grade 1
* Patients of childbearing potential must have a negative pregnancy test prior to the study entry and be practicing an effective form of contraception; sexually active subjects must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug, even if oral contraceptives are also used; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug; pregnant women are excluded from this study
* Patients must have signed an approved informed consent and authorization permitting the release of personal health information
* Patients must meet pre-entry requirements

Exclusion Criteria:

* Patients who have had previous treatment with cabozantinib; patients who have received previous treatment with weekly paclitaxel for recurrent or persistent disease
* Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer and other specific malignancies, are excluded if there is any evidence of other malignancy being present within the last three years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy
* Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis or thoracic cavity within the last three years are excluded; prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
* Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of ovarian, fallopian tube, or primary peritoneal cancer within the last three years are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
* Uncontrolled hypertension, defined as systolic greater than 140 mm Hg or diastolic greater than 90 mm Hg despite antihypertensive medications
* Myocardial infarction or unstable angina within 6 months prior to registration
* New York Heart Association (NYHA) class II or greater congestive heart failure
* History of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or serious cardiac arrhythmia requiring medication; this does not include asymptomatic atrial fibrillation with controlled ventricular rate
* Any history of congenital long QT syndrome
* The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms within 28 days before randomization; note: if initial QTcF is found to be \> 500 ms, two additional electrocardiogram (EKGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is =\< 500 ms, the subject meets eligibility in this regard
* Patients with serious non-healing wound, ulcer, or bone fracture within 28 days before treatment
* Patients with history of organ transplant
* Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving (in contact with, invading or encasing) major vessels
* Patients who have experienced any of the following:

  * Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
  * Hemoptysis of \>= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
  * Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
* Patients who have radiographic evidence of cavitating pulmonary lesion(s)
* Patients who have tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before treatment
* Gastrointestinal disorders, particularly those with potential risk of perforation or fistula formation including:

  * Any of the following within 28 days of registration

    * Intra-abdominal tumor/metastases invading GI mucosa
    * Active peptic ulcer disease
    * Inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
    * Malabsorption syndrome
  * Any of the following within 6 months of registration

    * Abdominal fistula
    * Gastrointestinal perforation
    * Bowel obstruction or gastric outlet obstruction; note: patients requiring drainage gastrostomy (e.g., percutaneous endoscopic gastrostomy \[PEG\] tube) and/or parenteral hydration and/or nutrition are not eligible
    * Intra-abdominal abscess; note: complete resolution of an intra-abdominal abscess must be confirmed prior to registration even if the abscess occurred more than 6 months prior to registration
* Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures which are not controlled with non-enzyme inducing anticonvulsants, any brain metastases and/or epidural disease, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months prior to the first date of study treatment
* The subject requires chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)
* Patients who are unable or unwilling to swallow tablets
* Patients who are pregnant or nursing
* The subject requires concomitant treatment, in therapeutic doses, with anti-coagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor Xa inhibitors or antiplatelet agents (i.e. clopidogrel); low dose aspirin (=\< 81 mg/day) low-dose warfarin (=\< 1 mg/day) and prophylactic low molecular weight heparin are permitted
* Major surgery within 3 months of the first dose of cabozantinib if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound complications
* Minor surgery within 1 month of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications
* Patients with concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment

Answer: C