Clinical Trial Results:
Phase II, randomised, placebo controlled, multicentre, feasibility study of low dose (metronomic) cyclophosphamide with or without nintedanib (BIBF 1120) in advanced ovarian cancer (METRO-BIBF)
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Summary
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EudraCT number |
2011-005814-12 |
Trial protocol |
GB |
Global end of trial date |
11 Jan 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Jan 2019
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First version publication date |
23 Jan 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
UCL10/0470
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01610869 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University College London
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Sponsor organisation address |
Gower Street, London, United Kingdom, WC1E 6BT
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Public contact |
Trial Co-ordinator, CR UK and UCL Cancer Trials Centre, +44 02076799237, ctc.metrobibf@ucl.ac.uk
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Scientific contact |
Trial Co-ordinator, CR UK and UCL Cancer Trials Centre, +44 02076799237, ctc.metrobibf@ucl.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
07 Nov 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
11 Jan 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Jan 2018
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The trial objectives are to explore the efficacy and safety of an all oral combination of nintedanib (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.
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Protection of trial subjects |
The first 12 patients randomised were reviewed for toxicity every three weeks for the first 12 weeks, the data was reviewed by the Independent Data Monitoring Committee (IDMC) and the dosage was considered acceptable and patients were assessed 6 weekly thereafter. The IDMC further reviewed toxicity data and serious adverse events (SAEs) in July 2015, and this resulted in a decision to reduce the starting dose of nintedanib/matching placebo to 150mg b.d.. Patients randomised at this starting dose were reviewed at 3 and 6 weeks and thereafter every 6 weeks. Patients received oral nintedanib and cyclophosphamide or cyclophosphamide and matched placebo continuously until disease progression, death or unacceptable toxicity.
Patient safety was monitored using regular patient assessments, dose modification guidance, regular review of safety data by the IDMC and Trial Management Group (TMG) and through strict eligibility criteria.
Patient data was stored in a secure manner and UCL CTC trials are registered in accordance with the Data Protection Act 1998 and the Data Protection Officer at UCL.
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Background therapy |
Patients were given a supply of a suitable antiemetic as per local guidelines, to take as required for any nausea experienced with cyclophosphamide. Some patients required steroids as per local guidelines, for symptom control and this was permitted as was any other medication such as analgesia or laxatives for palliation of symptoms. All concomitant medication was recorded. | ||
Evidence for comparator |
Cyclophosphamide has been used in the treatment of malignancies including breast and ovarian cancer for decades. All patients in the trial received cyclophosphamide +/- nintedanib. In ovarian cancer, angiogenesis has been shown to have a central role in both disease progression and prognosis. A direct relationship has been demonstrated between the expression of biomarkers for angiogenesis such as VEGF, the degree of neovascularization and the behaviour of epithelial ovarian cancers. These data suggest that pharmacological inhibitors of angiogenesis may have the capacity to arrest tumour progression. Several phase II trials of different antiangiogenic drugs have demonstrated activity against relapsed ovarian cancer. Nintedanib is a potent, orally available triple kinase inhibitor targeting VEGFRs, PDGFRs, and FGFRs. The specific and simultaneous abrogation of these pathways results in effective growth inhibition of both endothelial and, via PDGF- and FGF-receptors of perivascular cells, which may be more effective than inhibition of endothelial cell growth via the VEGF pathway alone. Furthermore, signalling by FGF-receptors has been identified as a possible escape mechanism for tumour angiogenesis when the VEGF pathway is disrupted. In addition preclinical models show that nintedanib may have a direct anti-tumour effect on those malignant cells which overexpress PDGFR and/or FGFR. Previous studies have shown that nintedanib is generally well tolerated with mild to moderate adverse effects such as gastrointestinal symptoms (nausea, diarrhoea, vomiting, abdominal pain) and reversible elevations of liver enzymes. A randomised phase II maintenance trial in ovarian cancer in which the efficacy and safety of nine months of continuous twice daily doses of nintedanib following chemotherapy was investigated, has identified the potential activity of nintedanib with a 36-week progression free survival (PFS) of 14.3 % compared to 5.0 % in the control group. | ||
Actual start date of recruitment |
26 Aug 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 117
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Worldwide total number of subjects |
117
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EEA total number of subjects |
117
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
62
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From 65 to 84 years |
55
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85 years and over |
0
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Recruitment
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Recruitment details |
117 patients were randomised from NHS hospitals across the UK between 26/08/2014 and 26/10/2016. 3 patients did not start the investigational drug and are excluded from this EudraCT submission. The planned recruitment end date was 01/10/2017 (with 124 patients), but recruitment was suspended early following IDMC review due to lack of efficacy. | |||||||||
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Pre-assignment
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Screening details |
- Medical History (must have had >2 lines chemotherapy for ovarian cancer) - Clinical examination - blood pressure, ECG, ECOG - CT/MRI scan - Liver function tests: AST and/or ALT, alkaline phosphatase, bilirubin and albumin - Haematology, coagulation parameters and biochemistry - Tumour marker (CA125) - Urinalysis for proteinuria | |||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator, Monitor, Carer, Assessor | |||||||||
Blinding implementation details |
Use of a matched placebo.
The IWRS/IVRS system was used for randomised allocation, trial medication assignment, initial drug supply of nintedanib/placebo and resupply, discontinuation from study treatment, emergency code breaks (i.e. unblinding) and trial drug shipment confirmation. The IWRS/IVRS technology was managed and maintained by Almac Clinical Technologies. The system was accessible via the internet 24 hours a day, 7 days a week.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Control Arm | |||||||||
Arm description |
Placebo and cyclophosphamide | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Cyclophosphamide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
50mg tablets b.d. - daily dose of 100mg. Continuous daily dosing until withdrawal criteria are fulfilled e.g. progression of disease, death, or unacceptable toxicity. New bottles of medication will be dispensed on day 1 of the first two 21-day cycles and then every 42-day cycle.
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Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, soft
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Routes of administration |
Oral use
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Dosage and administration details |
At randomisation the dose administered will be 150-200 mg twice daily of placebo (depending on the date the patient was randomised). Placebo will be provided in 150 mg and 100 mg capsules so, depending on date of randomisation, patients will either take two 100 mg capsules in the morning and another two capsules approximately 12 hours later OR one x 150mg capsule in the morning and another one approximately 12 hours later. Continuous daily dosing until withdrawal criteria are fulfilled e.g. progression of disease, death, or unacceptable toxicity. New bottles of medication will be dispensed on day 1 of the first two 21-day cycles and then every 42-day cycle.
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Arm title
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Investigation arm | |||||||||
Arm description |
Nintedanib and cyclophosphamide | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Cyclophosphamide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
50mg tablets b.d. - daily dose of 100mg. Continuous daily dosing until withdrawal criteria are fulfilled e.g. progression of disease, death, or unacceptable toxicity. New bottles of medication will be dispensed on day 1 of the first two 21-day cycles and then every 42-day cycle.
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Investigational medicinal product name |
Nintedanib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, soft
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Routes of administration |
Oral use
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Dosage and administration details |
At randomisation the dose administered will be 150-200 mg twice daily of nintedanib (depending on the date the patient was randomised). Nintedanib will be provided in 150 mg and 100 mg capsules so, depending on date of randomisation, patients will either take two 100 mg capsules in the morning and another two capsules approximately 12 hours later OR one x 150mg capsule in the morning and another one approximately 12 hours later. Continuous daily dosing until withdrawal criteria are fulfilled e.g. progression of disease, death, or unacceptable toxicity. New bottles of medication will be dispensed on day 1 of the first two 21-day cycles and then every 42-day cycle.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: As 3 patients did not start the study treatment, they have been excluded from the analysis. |
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Baseline characteristics reporting groups
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Reporting group title |
Control Arm
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Reporting group description |
Placebo and cyclophosphamide | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Investigation arm
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Reporting group description |
Nintedanib and cyclophosphamide | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety analysis
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
These are the 114 patients who started the study drug
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End points reporting groups
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Reporting group title |
Control Arm
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Reporting group description |
Placebo and cyclophosphamide | ||
Reporting group title |
Investigation arm
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Reporting group description |
Nintedanib and cyclophosphamide | ||
Subject analysis set title |
Safety analysis
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
These are the 114 patients who started the study drug
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End point title |
Overall survival | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Over the follow-up period
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Statistical analysis title |
Overall survival analysis | ||||||||||||
Comparison groups |
Investigation arm v Control Arm v Safety analysis
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Number of subjects included in analysis |
228
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.81 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.05
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
0.7 | ||||||||||||
upper limit |
1.57 | ||||||||||||
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End point title |
Progression free survival | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
over the follow-up period
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Statistical analysis title |
Progression-free survival analysis | ||||||||||||
Comparison groups |
Control Arm v Investigation arm v Safety analysis
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Number of subjects included in analysis |
228
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.61 | ||||||||||||
Method |
Regression, Cox | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.91
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
0.62 | ||||||||||||
upper limit |
1.32 | ||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
From informed consent to 30 days post last trial treatment administration.
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Adverse event reporting additional description |
Clinical assessment and self-reported patient diary.
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||
Dictionary version |
4.0
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| Frequency threshold for reporting non-serious adverse events: 0% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Full reporting of adverse events will be done via the publication in a scientific journal |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | ||||||||||
Date |
Amendment |
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25 Oct 2013 |
Filter Q2e amended in REC Application Form
Change of PI at Mount Vernon Hospital
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11 Dec 2013 |
Change of PI at St James’s University Hospital and Royal United Hospital |
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07 Apr 2014 |
Updated protocol v2.0, updated IB for nintedanib, updated SmPC for cyclophosphamide, pregnancy monitoring PIS and CF:
- Update to trial management group members
- Updates to summary of trial design
- Details of circulating tumour cell sub-study added (sponsored by East and North Herts NHS Trust). MRI sub-study removed
- Information on incidence of ovarian cancer updated
- PT removed as a coagulation parameter
- Total (rather than indirect) and Direct Bilirubin required if bilirubin elevated
- Total protein and calcium tests removed from screening assessments
- Albumin added as a screening assessment
- Clarification regarding treatment breaks added
- Clarification that patient must be 18 years or older to be eligible
- Clarification LMWH and warfarin treatment allowed (i.e. not an exclusion criteria), reference to in dwelling venous catheter removed.
- Clarification regarding INR ranges in the presence/absence of therapeutic anticoagulants-
- PT removed as a coagulation parameter.
- Amended- patients on therapeutic anticoagulants with APTT greater than 2.5xULN not eligible (previously 1.5xULN).
- Added extra information - poorly controlled diabetes mellitus or patient on sulphonylurea-type hypoglycaemics (e.g. glicazide) as main diabetic control (as contraindicated with cyclophosphamide)
- Clarified VEGF within 4 weeks of study treatment (rather than study start)
- Stratification factor – number of previous lines of chemotherapy corrected to ≤3 or >3
- Placebo added as IMP
- Clarification that patients can have a maximum of three treatment breaks of less than 21 days, if more they need to contact the UCL CTC to discuss continued treatment
- Clarification that re-screening must be performed for patients who have discontinued previous study treatment due to DLT or other adverse events for 21 to 30 days
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07 Nov 2014 |
Change of PI at St James’s University |
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14 Jul 2015 |
Urgent Safety Measure: trial recruitment halted following IDMC review requiring revision to protocol start dose for nintedanib |
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10 Sep 2015 |
Updated protocol v3 following urgent safety measure:
- Update to trial management group members
- Trial schema updated in line with new nintedanib start dose (150mg b.d.) and new week 3 safety visit
- Introduction updated with information from IB version 14 (19Jan2015); the outcome of the July 2015 IDMC review; results from trials that have reported since last protocol update.
- Clarification that there are no data available for patients with an inherited pre-disposition to bleeding or for patients receiving a full dose of anticoagulant treatment prior to starting treatment with nintedanib, therefore careful monitoring and caution is advised in this group of patients
- Secondary end point added to confirm response according to RECIST 1.1 and GCIG will be assessed where data available (as mentioned in inclusion criteria)
- Baseline MRI scan included as pre-randomisation evaluation if patient known to have stable brain metastases
- Urinalysis for proteinuria included in screening investigation table
- Clarification re-screening procedure in section 8.2 also needs to be followed if patient does not start treatment within 14 days of randomisation
- Updated in line with new nintedanib start dose (150mg b.d.) and new week 3 safety visit for all patients randomised after July 2015
- Clarification on eligibility criteria and randomisation procedure
- Further guidance added regarding dose modifications
- Nintedanib with dietary soya products are known to cause allergic reactions including severe anaphylaxis in persons with soya allergy. Patients with known allergy to peanut protein carry an enhanced risk for severe reactions to soya preparations
- Clarification to the emergency unblinding procedure
- 3 weekly assessment table removed as safety cohort closed and trial patients no longer on 3 weekly visits
- (6 weekly assessments) updated to include week 3 safety visit, check for germline BRCA mutation status (where information available) at baseline |
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27 Oct 2015 |
Updated investigator's brochure from Boehringer Ingelheim Ltd. |
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23 Sep 2016 |
Updated investigator's brochure from Boehringer Ingelheim Ltd. |
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08 Nov 2016 |
Recruitment suspension following IDMC recommendation. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | ||||||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | ||||||||||
| None reported | ||||||||||
