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Low Dose Cyclophosphamide +/-- Nintedanib in Advanced Ovarian Cancer (METRO-BIBF)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
University College, London
ClinicalTrials.gov Identifier:
NCT01610869
First received: November 25, 2011
Last updated: May 3, 2017
Last verified: December 2016
  Purpose
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.

Condition Intervention Phase
Ovarian Cancer Fallopian Tube Cancer Drug: BIBF 1120 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by University College, London:

Primary Outcome Measures:
  • Overall survival [ Time Frame: After follow-up is complete (year 3-4 of the trial) ]
    To be measured in days, from the date of randomisation to the date of death.


Secondary Outcome Measures:
  • Quality of life [ Time Frame: After follow-up is complete (year 3-4 of the trial) ]
    Health questionnaires which record qualitative health data on the patient perspective of their illness and treatment. This will be measured on a 6 weekly basis, from baseline to the end of treatment.

  • Adverse events for all patients [ Time Frame: After follow-up is complete (year 3-4 of the trial) ]
    Adverse events will be collected for patients in both groups during treatment and the groups compared during analysis. This will be measured on a 6 weekly basis, from baseline to the end of treatment. The first 12 patients will be assessed on a 3 weekly basis, from baseline to end of treatment.

  • Progression free survival [ Time Frame: After follow-up is complete (year 3-4 of the trial) ]
    Progression free survival will be determined by measurement of tumour size using RECIST 1.1 at progression or by a rise in CA-125 tumour marker. Measured from the date of randomisation until date of confirmed disease progression. Tumour assessment carried out on 3 monthly basis, CA-125 carried out on 6 weekly basis.


Estimated Enrollment: 124
Study Start Date: August 2014
Estimated Study Completion Date: October 2017
Estimated Primary Completion Date: October 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cyclophosphamide and BIBF-1120
Patients will receive oral BIBF 1120 (200mg bd) and cyclophosphamide (100mg) on a daily basis until disease progression or unacceptable toxicity.
Drug: BIBF 1120
Patients will receive either cyclophosphamide (100mg)and oral BIBF 1120 (200mg bd) or cyclophosphamide (100mg) and placebo.
Other Name: BIBF 1120 brand name: Nintedanib.
Placebo Comparator: Cyclophosphamide and placebo
Patients will receive oral BIBF 1120 (200mg bd) and placebo capsules on a daily basis until disease progression or unacceptable toxicity.
Drug: BIBF 1120
Patients will receive either cyclophosphamide (100mg)and oral BIBF 1120 (200mg bd) or cyclophosphamide (100mg) and placebo.
Other Name: BIBF 1120 brand name: Nintedanib.

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.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01610869

Locations
United Kingdom
Kent Oncology Centre
Maidstone, Kent, United Kingdom
Beatson West of Scotland Cancer Centre
Glasgow, Scotland, United Kingdom
Velindre Hospital
Cardiff, Wales, United Kingdom
Royal United Hospital
Bath, United Kingdom
Addenbrookes Hospital
Cambridge, United Kingdom
Royal Derby Hospital
Derby, United Kingdom
Mount Vernon Hospital
Greater London, United Kingdom
Royal Surrey County Hospital
Guildford, United Kingdom
St James's University Hospital
Leeds, United Kingdom
Clatterbridge Centre for Oncology
Liverpool, United Kingdom
Royal Marsden Hospital
London, United Kingdom
St Bartholomew's Hospital
London, United Kingdom
University College London Hospital (UCLH)
London, United Kingdom
Christie Hospital
Manchester, United Kingdom
Churchill Hospital
Oxford, United Kingdom
Wexham Park Hospital
Slough, United Kingdom
Sponsors and Collaborators
University College, London
Boehringer Ingelheim
Investigators
Principal Investigator: Dr Marcia Hall Mount Vernon Cancer Centre
  More Information

Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT01610869     History of Changes
Other Study ID Numbers: UCL/10/0470
2011-005814-12 ( Other Grant/Funding Number: Boehringer Ingelheim Ltd )
Study First Received: November 25, 2011
Last Updated: May 3, 2017
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by University College, London:
Recurrence
Ovarian Neoplasms
Ovarian Diseases
Fallopian Tube Neoplasms
Neoplasms
Carcinoma
Neoplasms by site

Additional relevant MeSH terms:
Ovarian Neoplasms
Fallopian Tube Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Fallopian Tube Diseases
Cyclophosphamide
Nintedanib
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Enzyme Inhibitors

ClinicalTrials.gov processed this record on June 28, 2017