Phase II, Randomised, Placebo Controlled, Multicentre, Feasibility Study of Low Dose (Metronomic) Cyclophosphamide With and Without BIBF 1120 in Advanced Ovarian Cancer
Inclusion Criteria:
- Female subjects, >18 years, histologically proven recurrent advanced ovarian,
fallopian tube or primary peritoneal carcinomas
- Performance status 0-2
- Adequate organ function
- Life expectancy > 6 weeks
- Has received 2 or more lines of chemotherapy
- No previous oral cyclophosphamide or Nintedanib, or other tyrosine kinase inhibitors
but may have had VEGF inhibitors
- At least 1 measurable lesion according to RECIST 1.1 criteria or any other baseline
prerequisite
- Declined any further standard IV chemotherapy
- Able to give written informed consent and to complete QoL
Exclusion Criteria:
- Malignant tumour of non-epithelial origin
- Clinically relevant non-healing wound, ulcer (intestinal tract, skin) or bone
fracture
- Symptoms or signs of GI obstruction requiring parenteral nutrition or hydration or
any other GI disorders or abnormalities that would interfere with drug absorption
- Active brain metastases (i.e.stable for < 4weeks, symptoms deteriorating) or
leptomeningeal disease. Trial entry is allowed if the brain metastases are stable.
Dexamethasone is allowed if administered as stable dose for at least one month before
randomisation
- Clinically relevant therapy-related toxicity from previous chemotherapy and
radiotherapy
- History of major thromboembolic event, such as pulmonary embolism or proximal deep
vein thrombosis, unless on stable therapeutic anticoagulation (aspirin <325mg daily
allowed as is low dose heparin for maintenance of in-dwelling venous catheter)
- Known inherited or acquired bleeding disorder
- Significant cardiovascular diseases
- 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:
- creatinine >1.5 x ULN or calculated GFR < 45 ml/min. Sites can use any
calculation method according to local practice.
- absolute neutrophil count (ANC) < 1.5x109/L
- platelets < 100 x109/L
- haemoglobin < 9.0 g/dL
- proteinuria CTCAE 2 or >
- total bilirubin > x 2 ULN
- ALT or AST > 1.5 x ULN unless liver metastases present when ALT / AST > 2.5 ULN
- International normalized ratio (INR)>2, prothrombin time (PT) and activated
partial thromboplastin time (APPT) > 50% of deviation of institutional ULN in
the absence of therapeutic anticoagulation
- Serious infections in particular if requiring systemic antibiotic
- Poorly controlled diabetes mellitus
- Other malignancy diagnosed within the past 5 years. In exception to this rule, the
following malignancies may be included:
- non-melanomatous skin cancer (if adequately treated)
- cervical carcinoma in situ (if adequately treated)
- carcinoma of the breast (if adequately treated >5 years ago)
- 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 that may increase the risk
associated with study participation or study drug administration
- Women of childbearing potential who are sexually active and not using a highly
effective method of birth control during the trial and for at least 3 months after
the end of active therapy
- Pregnancy and breastfeeding, female patients of childbearing potential must have a
negative pregnancy test prior to commencing study treatment.
- Psychological, familial, sociological or geographical factors potentially hampering
compliance with the study protocol and follow-up schedule
- Any contraindications for therapy with cyclophosphamide
- Chemotherapy, including immunotherapy or monoclonal antibody treatment (VEGF) within
4 weeks of study start. Hormones within 2 weeks of study start. Any previous
tyrosine kinase inhibitor treatment or radiotherapy of measurable evaluable disease
will make the patient ineligible.