Brief Title
Low Dose Cyclophosphamide +/-- Nintedanib in Advanced Ovarian Cancer
Official 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.
Detailed Description
A randomised placebo controlled double blind multi-centre phase II trial: BIBF 1120 200mg bd
plus 100mg daily of oral cyclophosphamide (experimental arm) or oral cyclophosphamide 100mg
daily plus placebo (control arm). Patients will receive oral BIBF 1120 and cyclophosphamide
or cyclophosphamide and placebo continuously until disease progression or unacceptable
toxicity.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Overall survival
Secondary Outcome
Quality of life and qualitative health data
Condition
Ovarian Cancer
Intervention
BIBF 1120
Study Arms / Comparison Groups
Cyclophosphamide and BIBF-1120
Description: Patients will receive oral BIBF 1120 (200mg bd) and cyclophosphamide (100mg) on a daily basis until disease progression or unacceptable toxicity.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
117
Start Date
August 2014
Completion Date
January 11, 2018
Primary Completion Date
January 11, 2018
Eligibility Criteria
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
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Dr Marcia Hall, ,
Location Countries
United Kingdom
Location Countries
United Kingdom
Administrative Informations
NCT ID
NCT01610869
Organization ID
UCL/10/0470
Secondary IDs
2011-005814-12
Responsible Party
Sponsor
Study Sponsor
University College, London
Collaborators
Boehringer Ingelheim
Study Sponsor
Dr Marcia Hall, Principal Investigator, Mount Vernon Cancer Centre
Verification Date
October 2018