Transcript Document

NiCCC (G143)
(ENGOT-GYN1)
A Randomised Phase II study Of Nintedanib (BIBF1120)
Compared To Chemotherapy in Patients With Recurrent Clear
Cell Carcinoma Of The Ovary Or Endometrium
EudraCT Number:2013-002109-73
ISRCTN50772895
INITIATION SLIDES
(Version 1.0, 15th July 2014)
Trial Details
•
The trial is an NCRN/Boehringer Ingelheim (BI), collaboration
•
The trial is being co-ordinated via the Cancer Research UK Clinical Trials Unit, Glasgow
•
Sponsor of the trial is Greater Glasgow Health Board (GGHB)
•
The trial will also open across Europe via collaborations with the EORTC, the NSGO and
ARCAGY-GINECO
•
The Chief Investigator is Dr Ros Glasspool of the Beatson West of Scotland Cancer Centre.
The International Chief Investigator is Dr Mansoor Mizra of Copenhagen University Hospital
•
The trial is being funded by an educational grant from Boehringer Ingelheim (who are also
providing drug supply of Nintedanib) and is endorsed by CTAAC (Cancer Research UK)
*******************************************************************
Please note this presentation has been prepared as part of your site initiation training. These
slides are a compliment to the protocol, all site staff must have read and understood the protocol
and the trial requirements prior to signing off the initiation acknowledgment sheet
*******************************************************************
NiCCC - Initiation Slides V1.0, 21Jul2014
2
Trial Team
•
Chief Investigator :
Dr Ros Glasspool
•
International Chief Investigator:
Dr Mansoor Mizra
•
Co-Investigator/
Translational Research Co-ordinator:
Professor Ian McNeish
•
trial Statistician:
Jim Paul
•
Project Manager:
Claire Lawless
•
Pharmacovigilance:
Lindsey Connery / Susannah Redford
•
Clinical Trial Coordinator:
Laura Douglas
•
Clinical Trial Monitor:
Calum Innes
NiCCC - Initiation Slides V1.0, 21Jul2014
3
Trial Design
A multi-centre, randomised, open label phase II trial
90 patients with progressive or recurrent clear cell ovarian and up to 30 patients
with clear cell endometrial cancer
Registration
Central Pathology Review Criteria
and Eligibility Criteria met
Randomisation
Control Arm
Experimental Arm
Physicians choice of standard chemotherapy,
from list below*.
Nintedanib 200mg BD continuously until progression or
withdrawal from trial
Assessments
Assessments
Clinical:
At screening, Day 1 of each course of chemotherapy
CA125:
At screening and day 1 of each cycle during treatment then every 8
weeks until progression
CT Scans
Screening, and every 8 weeks until week 48 or until progression
Clinical:
At screening, Day 1 and then every 4 weeks until week 24
and then every 8 weeks.
CA125:
At screening, day 1 and every 4weeks until week 24 then
every 8 weeks until progression
CT Scans
Screening, and every 8 weeks until week 48 or until
progression
Primary Endpoint: PFS
Secondary Endpoints: OS, QoL, QTWIST, ORR, & DCR at 12 weeks
NiCCC - Initiation Slides V1.0, 21Jul2014
4
Control Arm
• Chemotherapy options – Investigator decision
Standard Chemotherapy choice:
Ovarian Cancer Patients (all chemotherapy regimens are 4-weekly):
Paclitaxel (80mg/m2) IV Day 1, 8, 15 every 28 days, up to 6 cycles
PLD (40mg/m2) IV every 28 days, up to 6 cycles
Topotecan 4mg/m2 IV Day 1, 8, 15 every 28 days, up to 6 cycles
Endometrial Cancer Patients (all chemotherapy regimens are 3-weekly):
Carboplatin (AUC 5) and Paclitaxel (175mg/m2) IV q21, up to 6 cycles
Doxorubicin IV 60mg.m2 every 21 days, up to 6 cycles
NiCCC - Initiation Slides V1.0, 21Jul2014
5
Population and Aims
Trial population
• 120 patients with progressive or recurrent ovarian clear cell carcinoma, or progressive or
recurrent endometrial clear cell carcinoma. The primary diagnosis must be histologically
confirmed and central pathological review of the presenting tumour or biopsy of relapsed
disease must find at least 50% clear cell carcinoma with no serous differentiation
Trial Aims
Primary Objective:
• The primary endpoint for efficacy is progression free survival as defined by RECIST 1.1
criteria. Progression free survival (PFS) is defined as the duration of time from date of
randomisation to date of progression or death, which ever occurs earlier
Secondary Objectives:
• Overall survival (OS) Patients will be followed up to the end of the trial period.
• Overall Response Rate (ORR). Best response rate will be determined according to combined
GCIG criteria
• Disease Control Rate (DCR = Complete Response, Partial Response and Stable Disease) at 12
weeks
• Toxicity. Adverse event data will be collected during the treatment phase of the trial
• Quality of Life. Patients will be asked to complete 4 questionnaires (EORTC QLQ C30,OV28,
MOST and EQ-5D).
• Q-TWiST (Quality-Adjusted Time Without Symptoms of Disease or Toxicity of Treatment) will
balance quality and quantity of time by combining survival data with EQ-5D quality of life
data
NiCCC - Initiation Slides V1.0, 21Jul2014
6
Trial Eligibility
Inclusion Criteria:
1.
Progressive or recurrent ovarian clear cell carcinoma, or progressive or recurrent endometrial
clear cell carcinoma. The primary diagnosis must be histologically confirmed and central
pathological review of the presenting tumour or biopsy of relapsed disease must find at least
50% clear cell carcinoma with no serous differentiation. Progressive disease as defined by
RECIST 1.1
2.
Failure after ≥1 prior platinum containing regimen which may have been given in the adjuvant
setting. For patients with ovarian clear cell carcinoma, progression must have occurred within 6
months of their last platinum dose
3.
ECOG Performance status of ≤2
4.
Life expectancy of >3 months
5.
Adequate hepatic, bone marrow coagulation and renal function
-Hepatic function: total bilirubin within normal limits; ALT and AST < 2.5 x ULN
-Coagulation parameters: INR <2 x ULN and prothrombin time and activated partial
thromboplastin time < 1.5 x ULN in the absence of therapeutic anticoagulation
-Absolute neutrophil count (ANC) ≥1.5 x 109/L
-Platelets ≥ 100 x 109L
-Haemoglobin ≥ 9.0 g/dL
-Proteinuria < grade 2 (CTCAE version 4)
-Glomerular Filtration Rate ≥40ml/min. (calculated using Cockroft & Gault equation or
measured by EDTA clearance)
6.
Female and > 18 years of age
7.
Signed and dated written informed consent prior to admission to the trial in accordance with
ICH-GCP guidelines and local legislation.
8.
Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests
and other trial procedures.
NiCCC - Initiation Slides V1.0, 21Jul2014
7
Trial Eligibility
Exclusion Criteria:
1.
Prior treatment with Nintedanib or other angiogenesis inhibitor/VEGF targeted therapy, except for
prior treatment with bevacizumab which is permitted
2.
Treatment within 28 days prior to randomisation with any investigational drug, radiotherapy,
immunotherapy, chemotherapy, hormonal therapy or biological therapy Palliative radiotherapy may
be permitted for symptomatic control of pain from bone metastases in extremities, provided that the
radiotherapy does not affect target lesions, and the reason for the radiotherapy does not reflect
progressive disease
3.
Previous treatment with the chemotherapy regimen selected as the control arm by the investigator.
(Prior therapy with paclitaxel given on a three weekly regimen is permitted for patients receiving
weekly Paclitaxel)
4.
Other malignancy diagnosed within 5 years of enrolment except for:
a)
Non-melanomatous skin cancer (if adequately treated)
b)
Cervical carcinoma in situ (if adequately treated)
c)
Carcinoma in situ of the breast (if adequately treated)
d)
For patients with ovarian clear cell cancer, prior or synchronous endometrial cancer (if
adequately treated), provided all of the following criteria are met:
•
Disease stage FIGO Stage 1a (tumour invades less than one half of myometrium)
•
Grade 1 or 2
5.
Patients with any other severe concurrent disease, which may increase the risk associated with trial
participation or trial drug administration and, in the judgement of the investigator, would make the
patient inappropriate for entry into this trial, including significant neurologic, psychiatric, infectious,
hepatic, renal, or gastrointestinal diseases or laboratory abnormality
6.
Symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any
other gastro-intestinal disorders or abnormalities, including difficulty swallowing, that would interfere
with drug absorption
7.
Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral
therapy, including known hepatitis B and/or C infection and HIV-infection
8.
Symptomatic CNS metastasis or leptomeningeal carcinomatosis
NiCCC - Initiation Slides V1.0, 21Jul2014
8
Trial Eligibility
Exclusion Criteria continued:
9. Known, uncontrolled hypersensitivity to the investigational drugs or their excipients
10. Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac
arrhythmia, unstable angina or myocardial infarction within 6 months prior to randomisation, congestive
heart failure > NYHA III, severe peripheral vascular disease or clinically significant pericardial effusion
11. History of major thromboembolic event defined as:
• pulmonary embolism (PE) within six months prior to randomisation
• recurrent pulmonary embolism (history of at least 2 events)
• history of at least 2 unprovoked (=without a transient reversible risk factor) events of proximal deep
venous thrombosis
• history of a provoked (=with transient or reversible risk factor, such as surgery) thrombosis of
proximal deep veins or visceral vessels within 6 months prior to randomisation if not on stable
therapeutic anticoagulation
12. Prior thrombosis or thromboembolic event in the presence of an inherited coagulopathy (including
deficiency of antithrombin, deficiency of protein C or protein S, Factor V Leiden mutation or prothrombin
G20210A mutation)
13. Known inherited predisposition to bleeding or thrombosis
14. History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the
past 6 months
15. History of clinically significant haemorrhage in the past 6 months
16. Major injuries or surgery within the past 28 days prior to start of trial treatment with incomplete wound
healing and/or planned surgery during the on-treatment trial period
17. Pregnancy or breastfeeding. Patients with preserved reproductive capacity must have a negative
pregnancy test (β-HCG test in urine or serum) prior to commencing trial treatment
18. Patients with preserved reproductive capacity, unwilling to use a medically acceptable method of
contraception for the duration of the trial and for 3 months afterwards
19. Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels
20. Any psychological, familial, sociological or geographical consideration potentially hampering compliance
with the trial protocol and follow up schedule; those considerations should be discussed with the patient
9
before registration in the trial
NiCCC - Initiation Slides V1.0, 21Jul2014
Site Set Up
CTU GLASGOW
Main REC approval - MHRA approval - Site Initiation Slides
- Investigator File - Pharmacy File

SITE
Delegation Log – SSI - R&D Approval
- CVs and GCP certificates for PI and Lead Pharmacist - Clinical Trial
Agreement - PIS, Consent, GP Letter etc on Trust Headed paper
- Lab normal ranges (Haem + Biochem), Accreditation certificates.

INITIATION PROCESS

DRUG SUPPLY OF NINTEDANIB

SITE ACTIVATED
NiCCC - Initiation Slides V1.0, 21Jul2014
10
Informed Consent Process
Informed consent process:
•
Two original Consent Forms must be completed by a clinician (or deputy listed on delegation log)
•
Two originals signed and completed by the patient
•
Date must be prior to registration/ randomisation.
•
Make one photocopy
- Original to be filed in Investigator File
- Original to be given to patient (+PIS)
- Photocopy to be filed in hospital notes
•
Consent Form must not be sent to the Clinical Trials Unit
FOR ERRORS NOTED AFTER CONSENT
•
Add explanatory note/file note
•
New version of Patient Information Sheet must be provided to patients consented with previous version. This must be given
to all patients regardless of treatment stage, during next possible clinic visit.
•
Patients who are still on active treatment will be required to repeat the consent process using the updated form. If it is not
appropriate to re-consent patient (i.e. patient terminally ill) please make a note regarding this in the patients case notes and
on re- consent log which is filed in your trial site file.
CONSENT WITHDRAWAL
When the patient specifically asks to withdraw their consent at any point in the trial. If this occurs:
•
•
•
•
Document clearly in the patient notes that the patient has withdrawn consent, the level of consent withdrawal and the
reason (if the patient has given any)
Complete the consent withdrawal notification form ;
Send the consent withdrawal notification form to the CRUK CTU
No further follow-up should be collected on the patient from that point onwards.
NiCCC - Initiation Slides V1.0, 21Jul2014
11
Registration Process
•
All patients must be registered onto the trial prior to commencement of any trial procedures,
and central pathological review to confirm patient’s eligibility
•
Check that patient has given written informed consent as per the informed consent process.
•
Complete Registration Form.
•
Site staff must contact the Cancer Research Clinical Trials Unit, Glasgow to register the
patient. Registration to the trial can be done by either telephone or fax on the following
numbers:
Tel no: ++ 44 141 301 7215
Fax no: ++ 44 141 301 7219*
08.30-17.00 Monday - Thursday
08.30-16.30 Friday, except public holidays
* Faxes received outside of office hours will be processed the next working day
•
Each patient registered will be allocated a unique 3 digit sequential patient ID number for the
trial.
NiCCC - Initiation Slides V1.0, 21Jul2014
12
Process for UK Central Pathology Review
•
Once patients are identified and have given informed consent, a central pathology
review will be performed in order to confirm patient eligibility. Patients must first
be registered for the trial to allow central pathology review to be performed
•
The information collected on Registration Form will be passed to lead Pathologist
for trial in UK, who will contact the local pathologist and discuss the case and
ascertain if the basic criteria are reached
•
If the basic criteria are reached a request for 3 sets of the 3 most representative
slides should be scanned as digital images and sent via email to the 3 reviewing
pathologists for the trial. A scanned copy of the completed patient Registration
Form should also be provided. If it is not possible to provide digital images of the
slides, alternatively a single set of representative slides can be sent
•
The slides will be reviewed and agreement reached as to whether the accepted
criteria is met. A majority decision will be acceptable
•
The review decision will be emailed to the CRUK UK Clinical Trials Unit, Glasgow
who will subsequently inform the site
•
Patients who meet the accepted criteria will then be able to be randomised to the
trial, following completion of randomisation form
NiCCC - Initiation Slides V1.0, 21Jul2014
13
Randomisation Process
•
Check that central pathology review has confirmed patient as eligible
•
Check that patient fulfils all additional eligibility criteria as per trial protocol
•
Complete Randomisation Form
•
Site staff must contact the Clinical Trials Unit, Glasgow to randomise the patient.
Randomisation to the trial can be done by either telephone or fax on the following
numbers:
Tel no: ++ 44 141 301 7215
Fax no: ++ 44 141 301 7219*
08.30-17.00 Monday - Thursday
08.30-16.30 Friday, except public holidays
* Faxes received outside of office hours will be processed the next working
day
•
Each patient randomised will be allocated a unique 4 digit sequential patient ID
number for the trial
NiCCC - Initiation Slides V1.0, 21Jul2014
14
Pre Randomisation Evaluations
Prior to commencing any trial related procedures, all participants will be fully informed about the risks, benefits and
procedures involved in trial participation, and will sign a consent form confirming this process. All patients will then
undergo a period of screening during the 28 days prior to initiation of trial treatment.
Screening will consist of:
•
•
•
•
•
•
Complete medical history
Concomitant medication
Physical examination including weight, height and performance status
Baseline symptoms and toxicity assessment
Disease evaluation - CT or MRI of chest pelvis and abdomen reported to RECIST v1.1 and CA125
Central Pathology review
In addition, during the 14 days prior to initiation of trial treatment all patients will undergo the following evaluations:
•
•
•
•
•
•
•
•
•
Vital signs: Blood pressure , Pulse
ECG
Urinalysis (Dipstick)
ECOG Performance Status
Pregnancy test (only in those with preserved reproductive capacity)
Translational blood samples*
QoL assessments
Serum biochemistry
Haematology, including FBC and COAG
Protocol treatment must commence within 14 days of registration.
* Only applicable for patients participating in the translational component of the trial.
NiCCC - Initiation Slides V1.0, 21Jul2014
15
Treatment and Duration
•
Control Arm
The chemotherapy regimen will be physician’s choice from the list below.
The planned regimen (if allocated to the control arm) must be declared prior
to randomisation:
•
Ovarian Cancer Patients:
Paclitaxel (80mg/m2) IV Day 1, 8, 15 every 28 days, x6 cycles
Pegylated Liposomal Doxorubicin (PLD) (40mg/m2) IV every 28 days, x6 cycles
Topotecan (4mg/m2) IV Day 1, 8, 15 every 28 days, x6 cycles
•
Endometrial Cancer Patients:
Carboplatin (AUC 5) and Paclitaxel (175mg/m2) IV every 21 days, x6 cycles
Doxorubicin IV (60mg/m2) every 21 days x6 cycles
•
Experimental Arm
Nintedanib (BIBF1120) 200mg twice daily PO, continuously, until progression
or withdrawal from the treatment.
NiCCC - Initiation Slides V1.0, 21Jul2014
16
Nintedanib Dose Delays
•
Treatment with Nintedanib has to be interrupted if any of the criteria listed below are fulfilled:
NiCCC - Initiation Slides V1.0, 21Jul2014
17
Nintedanib Dose Reductions
•
After interruption of Nintedanib the following criteria must be met to restart Nintedanib:
•
GI adverse events:
•
Liver enzyme elevations: -bilirubin values CTCAE grade 0
-AST and ALT CTCAE grade ≤1
•
Neuropathy:
•
Other non-haematological adverse events:
-other non-haematological adverse which are considered drug-related have recovered to less
than or equal to the patient's pre-therapy value at trial enrolment
•
Nintedanib - Dose Modification for Toxicity
-nausea CTCAE grade ≤1
-vomiting CTCAE grade 0
-diarrhoea CTCAE grade ≤1
-neuropathy CTCAE grade ≤2
NiCCC - Initiation Slides V1.0, 21Jul2014
18
Nintedanib Compliance
• Empty Nintedanib bottles and any remaining medication is to be returned
at each patient visit
• These are then returned to pharmacy where a count takes place
• Sites will need to have a local process where pharmacy and research staff
review patient returns in a timely manner in order to assess patient
compliance
• Over or under compliance should be escalated to the trial team
• Patients will be provided with Nintedanib Diary Card to record their
compliance
NiCCC - Initiation Slides V1.0, 21Jul2014
19
Trial Restrictions
•
•
•
•
•
•
•
•
•
Additional chemo-, immuno-, hormone- or radiotherapies are not allowed during except for
palliative radiotherapy for symptomatic control of pain from bone metastases in extremities. To be
discussed with CI.
Treatment < 28 days prior to randomisation with any investigational drug is not permitted.
Patients must not be recruited to any IMP trials that involve an IMP while on NiCCC protocol
treatment, and during the follow up period prior to recurrence.
Debulking surgery is not permitted on the trial prior to progression.
Any invasive procedures such as minor or major surgery should be postponed to at least 4 weeks
after the end of treatment with Nintedanib.
For urgent interventions, Nintedanib should be interrupted 2 weeks prior to the procedure and
not be started before wound healing is complete.
If patients require emergency surgery, Nintedanib should be stopped as soon as the procedure is
planned and, if possible, at least 48 hours prior to the procedure.
Concomitant therapy with the 5-HT3 receptor antagonists tropisetron and/or dolasetron which are
metabolized by cytochrome 2D6 should be avoided in patients on Nintedanib since they may lack
efficacy in patients who are ‘fast metabolizers’.
During treatment with Nintedanib, all trial patients will be advised to avoid sun exposure or
artificial UVA/UVB radiation in solaria or tanning booths. If exposure to sunlight cannot be avoided,
protective clothing and broad spectrum (UVA/UVB) sunscreens should be used. After
discontinuation of Nintedanib treatment all protective measures should be continued for at least 2
weeks
NiCCC - Initiation Slides V1.0, 21Jul2014
20
Contraception
• Patients will be considered to be of childbearing potential unless surgically
sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or
post-menopausal for at least two years.
• Patients of child bearing potential who are sexually active must consent to
use a highly effective method of birth control for the duration of the trial
and for at least 3 months after the end of active therapy.
• A highly effective method of birth control is defined as one which results
in a low failure rate (i.e. less than 1% per year) when used consistently
and correctly, some intrauterine devices (IUDs), sexual abstinence or
vasectomised partner.
• Hormonal contraceptives should not be used for this trial. Intrauterine
systems (IUS) that release hormones are not allowed. The methods of
contraception used must be stated in the patient’s medical notes and
CRFs.
• If a patient becomes pregnant during the trial, the CRUK CTU must be
informed immediately.
NiCCC - Initiation Slides V1.0, 21Jul2014
21
Pregnancy Reporting
• In the event of a pregnancy, a Pregnancy Notification Form (PNF) must
sent to CRUK Clinical Trials Unit CTC within 24 hours
•
The pregnancy should be followed by site to follow pregnancy until term
•
Any changes in pregnancy such as miscarriage, termination, or birth
should be added to the PNF and sent to CRUK Pharmacovigilance as soon
as possible
• If at birth, there is found to be a defect or congenital anomaly then this
will also require immediate reporting to CRUK CTU Pharmacovigilance as a
SAE
NiCCC - Initiation Slides V1.0, 21Jul2014
22
Translational Research
Translational research will be conducted at 3 levels; centres will select their level of participation.
• Level 1 Research:
Formalin Fixed Paraffin Embedded Tissue Blocks from original primary surgery
Archival formalin-fixed, paraffin-embedded surgical/biopsy specimens of the original primary
tumour will be collected. Only ‘surplus’ tissue will be collected, i.e. surplus to diagnostic
requirements.
Blood Samples for Circulating Endothelial Cells
A sample will be collected at screening or day 1 of cycle 1, on day 1 of cycle 2, and at the end of
treatment visit.
• Level 2 Research: Level 1 samples plus the following:
Plasma Samples
A sample will be collected at baseline, on day 1 of each cycle, end of treatment visit, follow-up
visits and at progression.
Plasma Samples for Circulating Tumour DNA
A sample will be collected at baseline, on day 1 of each cycle, end of treatment visit, follow-up
visits and at progression.
NiCCC - Initiation Slides V1.0, 21Jul2014
23
Translational Research
•
Level 3 Research: Level 2 samples plus the following:
Tumour Biopsies
Women who consent to additional biopsies will undergo an image-guided tumour biopsy after
giving informed consent at least one week prior to starting trial treatment. With continued
consent they will have a further biopsy at disease progression.
•
Baseline blood samples may be taken at screening or on day 1 of cycle 1 prior to treatment.
•
Samples for circulating endothelial cells will be sent on the day of sampling to the Laboratory
of Translational Tumour Immunology, Department of Medical Oncology, Erasmus MC Cancer
Institute, Rotterdam, The Netherlands.
•
All other samples will be processed and stored at site and shipped in batches.
•
The samples must be collected for all patients who have consented to the translational
aspects of the trial on the consent form, please ensure all samples are taken for all consenting
patients
NiCCC - Initiation Slides V1.0, 21Jul2014
24
Drug Induced Liver Injuries (DILIs)
•
•
•
•
•
•
Detection of Drug-induced liver injury (DILI) has become an important aspect of patients’ safety guarding
in drug development
Any potential DILI has to be reported in an expedited manner to the FDA and be followed-up
appropriately, by Boehringer Ingelheim (BI). The follow-up includes a detailed clinical evaluation and
identification of possible alternative diseases (e.g. Hepatitis B) and/or other concomitant therapies that
might potentially be hepatotoxic.
Although rare, a potential for drug-induced liver injury is under constant surveillance by sponsors and
regulators. Therefore, this trial requires timely detection, evaluation, and follow-up of laboratory
alterations of selected liver laboratory parameters to ensure patients´ safety
The concept below has been worked out by BI in order to guard patient´s safety and to respond to
regulatory requirements:
Definition
The following changes in the laboratory values are considered to be a protocol-specific significant adverse
event for all patients with:
 an elevation of ALT and / or AST > 5x ULN without bilirubin elevation measured in the same blood
draw sample
 an elevation of AST and/or ALT >2.5 fold ULN combined with an elevation of bilirubin to >1.5 fold
ULN measured in the same blood draw sample
Patients showing these laboratory abnormalities need to be followed up until the protocol specific
retreatment criteria have been met
NiCCC - Initiation Slides V1.0, 21Jul2014
25
Potential DILI Evaluation & Follow Up Procedures - 1
Procedures
•
Stop Nintedanib
•
Protocol specified significant events are to be reported in an expedited manner similar to Serious Adverse
Events, even if they do not meet any of the seriousness criteria and documented in the CRF
•
Repeat the following laboratory tests for confirmation within 48 hours:
– AST and ALT, bilirubin measurement (total and direct bilirubin), Alkaline Phosphatase, Haptoglobin
assay, complete blood count and cell morphology, reticulocyte count, CK, LDH
•
The results of these repeated laboratory tests must be documented on the DILI Checklist Form (Part 1)
and reported to CRUK CTU Pharmacovigilance as soon as they are available.
•
An evaluation of the patient within 48 hours with respect to but not limited to:
– Abdominal ultrasound or clinically appropriate other imaging and investigations adequate to rule out
biliary tract, pancreatic, intra- or extrahepatic pathology, e.g. bile duct stones, neoplasm, hepatic
tumour involvement, biliary tract, pancreatic or intrahepatic pathology, vascular hepatic conditions
such as portal vein thrombosis or right heart failure.
– detailed history of current symptoms and concurrent diagnoses and medical history of concomitant
drug use (including non-prescription medications, herbal and dietary supplement preparations and
eg steroids as concomitant supportive treatment), alcohol use, recreational drug use, and special
diets detailed history of exposure to environmental chemical agents
NiCCC - Initiation Slides V1.0, 21Jul2014
26
Potential DILI Evaluation & Follow Up Procedures - 2
•
•
If neither imaging nor laboratory values suggest that cholestasis is the reason for ALT / AST
increase, and in particular if AlkPhos < 2x ULN, the following laboratory tests should be
performed within 7 days of the DILI first being reported, and results should be recorded on
the DILI Checklist Part 2:
Clinical chemistry
–
–
–
–
•
Alkaline phosphatase, cholinesterase (either plasma or red blood cell), albumin, PT or INR, CK, CKMB, transferrin, ferritin, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-HCV, RNA if
Anti-HCV positive), Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, IgM), herpes
simplex virus (IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM)
Perform repeat testing of ALT, AST, bilirubin (with fractionation into total and direct) and Alk Phos at
least weekly until the laboratory values return to normal or to the values as defined in the protocol.
If, despite stopping Nintedanib, the ALT, AST and bilirubin are NOT returning to normal levels
at the first weekly retest, and if all other liver tests are normal – i.e. no other cause for liver
dysfunction identified then perform: coeruloplasmin, α-1 antitrypsin, amylase, lipase, fasting
glucose, Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-HEV
IgM positive), Anti-Smooth Muscle antibody (titer), Anti-nuclear antibody (titer), Anti-LKM
(liver-kidney microsomes) antibody, Anti-mitochondrial antibody,TSH, Thrombocytes,
eosinophils
NiCCC - Initiation Slides V1.0, 21Jul2014
27
Potential DILI Evaluation & Follow Up Procedures - 3
•
If transaminases and/or bilirubin increase despite cessation of the experimental therapy,
more frequent intervals of testing will be required (as per local practice guidelines)
•
Depending on further laboratory changes, additional parameters identified e.g. by reflex
testing will be followed up based on medical judgement and Good Clinical Practices
•
Nintedanib should only be restarted if all liver function tests return to levels specified for the
treatment specified in the protocol. If a patient’s liver function tests recover and another
cause of their liver dysfunction is found, i.e. DILI is excluded, and the investigator wishes to
restart Nintedanib, this should be discussed with the chief investigator first who will also
discuss with the BI medical advisor
NiCCC - Initiation Slides V1.0, 21Jul2014
28
Reporting radiological investigations
to RECIST Criteria
• All radiological investigations must be reported as per
protocol / RECIST version 1.1
• Source documentation of this must be available for review if
the original report has had to be supplemented to bring it in
line with protocol requirements
• CTU, Glasgow have produced a worksheet to assist with the
documentation of trial specific reporting and will make this
available to any participating site upon request to the trial
monitor
NiCCC - Initiation Slides V1.0, 21Jul2014
29
QoL Questionnaires
• Patients will be asked to complete 4 questionnaires: EORTC QLQ C30,
OV28, MOST and EQ5D
• QoL assessments will be performed at screening, and on day 1 of cycle 2, 4
and 6
• For patients on the chemotherapy arm, QoL assessments will be
performed at the end of treatment visit and every 8 weeks on follow up
• For patients on Nintedanib arm, QoL assessments will be performed at day
1 of every cycle from cycle 7 onwards, at the end of treatment visit and
every 8 weeks on follow up
• QoL assessments will continue every 2 months post progression as long as
the PI considers it appropriate and the patient continues to consent
NiCCC - Initiation Slides V1.0, 21Jul2014
30
Patient Alert Cards
• A template Patient Alert Card will be provided for use, to be given to all patients
• Patients should be encouraged to carry the card on their person throughout their
participation in the trial and for at least 30 days after the last dose of trial drug
• The patient should present the card to any healthcare provider she sees and
should advise her family that she is carrying the card so that in the event that the
patient is seriously ill they can present the card to the healthcare provider on the
patient’s behalf
• The card will be provided by the recruiting site and will contain local contact
details
• The patient should be requested to return their Patient Alert Card to site staff
during follow up once they are 30 days post treatment
completion/discontinuation.
NiCCC - Initiation Slides V1.0, 21Jul2014
31
Patient Diary Cards
• A template Patient Diary Card will be provided for use, to be given to all patients
randomised to receive Nintedanib
• The patient should be given a Diary Card at the beginning of each treatment
cycle, and instructed to use this to record at what time each day they took their
Nintedanib capsules, or if they took an in correct doses or missed any doses.
• The Diary Card should be returned to site staff at the next visit and retained as
source documentation for Nintedanib compliance
• The card will be provided by the recruiting site and will contain local contact
details
NiCCC - Initiation Slides V1.0, 21Jul2014
32
CRFs
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Consent Notification Form
Registration
Randomisation Form
Baseline Form
QLQ C30 and OV28 QoL Form
EQ-5D QoL Form
MOST QoL Form
Treatment Form – Chemotherapy
Treatment Form – Nintedanib
Response Form
Follow–up Form
Concomitant Medication Form
Consent Withdrawal Notification Form
DILI Checklist Form Part 1
DILI Checklist Form Part 2
Pregnancy Notification Form
SAE Form Please note the SAE form is faxed to Pharmacovigilance at CTU and the
original SAE report is kept at site.
NiCCC - Initiation Slides V1.0, 21Jul2014
33
CRF Completion
•
•
•
•
•
•
•
•
CRF completion guidelines for the trial are currently being developed and will provided to sites when
available
Entries to the CRFs will be made in black ball-point pen and must be legible
Correction fluid etc. must not be used
Any errors must be crossed out with a single stroke, correction inserted and change initialled and dated
An explanation can be written next to amendment if necessary
Date format: DD/ MON/ YYYY
Please ensure all data submitted on the CRFs is verifiable in source documents
Take photocopy of all completed CRFs. Originals to be sent to CRUK CTU Glasgow
CRF completion timelines:
Timelines for entry
of required data in the CRF
Timelines for resolution of
data queries
Timelines for receipt of
CRFs at CRUK CTU, Glasgow
Within 4 weeks of patient
visit
Within 4 weeks of receipt
Within 2 weeks of form
completion
NiCCC - Initiation Slides V1.0, 21Jul2014
34
Pharmacovigilance
Clinical Trial Regulations require:
•
Investigators document Adverse Events (AEs) in patient notes and the CRF
•
Investigators report Serious Adverse Events (SAEs) immediately to the CRUK Clinical
Trials Unit, Glasgow (CTU)
•
Expedited reports of Suspected Unexpected Serious Adverse Reactions (SUSARs) are
reported to the Regulatory Authority in the occurrence country (the CTU, on behalf of
the Sponsor, will submit SUSAR reports to the appropriate Regulatory Authority and
with the assistance of collaborating groups, submit as per local requirements to the
Regulatory Authorities of non-occurrence countries, RECs and Investigators. Additionally
BI & the overall trial Sponsor will also receive a copy of any SUSAR reports)
•
A Development Safety Update Report (DSUR) is prepared and submitted annually to the
Regulatory Authorities and RECs of the countries in which the trial is being conducted
(the CTU will produce a DSUR on behalf of the Sponsor and circulate it to the
collaborative groups for onward transmission to Regulatory Authorities, RECs and
investigators as per local requirements. BI will also receive a copy of the DSUR)
NiCCC - Initiation Slides V1.0, 21Jul2014
35
Adverse Event Reporting
• All AEs must be followed:
- until resolution,
- or for at least 30 days after discontinuation of trial medication,
- or until toxicity has resolved to baseline,
- or < Grade 1,
- or until toxicity is considered to be irreversible
• All AE and toxicities must be graded according to the NCI-CTCAE Version
4.0
• An exacerbation of pre-existing condition is an AE
• Any AEs that are related to disease progression should be reported as
unrelated to the trial drugs (chemotherapy/Nintedanib). AEs that appear
as related to disease progression that are recorded as related to the trial
drugs will be queried by CRUK CTU Pharmacovigilance
NiCCC - Initiation Slides V1.0, 21Jul2014
36
Definition of a SERIOUS ADVERSE EVENT
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence, not
necessarily related to protocol treatment, that:
•
•
•
•
•
•
Results in death
Is life-threatening
Requires hospitalisation or prolongation of existing hospitalisation
Results in persistent or significant disability or incapacity
Consists of a congenital anomaly or birth defect
Is considered medically significant by the Investigator
•
Additionally for the NiCCC trial, any event which meets the criteria of a AE of special
interest (AESI) must also be reported within 24 hours on a SAE report form. Some AESIs
will also meet the criteria of a SAE as noted above and will be processed as a SAE.
However all AESI must be reported within 24 hours on a SAE report form whether the SAE
criteria is met or not.
NiCCC - Initiation Slides V1.0, 21Jul2014
37
Definition of a SERIOUS ADVERSE EVENT
Life threatening:
• The patient is at immediate risk of death from the event as it occurred. It
does not include an event that, had it occurred in a more serious form,
might have caused death
Requires in-patient hospitalisation:
• Is as a hospital admission required for treatment of an adverse event even
when the adverse event is not related to the protocol treatment
NiCCC - Initiation Slides V1.0, 21Jul2014
38
AEs of Special Interest
•
•
Although not necessarily meeting the definition of a SAE, the following AEs of special interest
(AESIs) must be reported on both the CTU and BI SAE Report within 24 hours according to
the SAE reporting procedures specified above:
Any gastrointestinal and non gastrointestinal perforation, leakage, fistula formation, abscess.
In such a case the following additional information must be collected, documented in the
respective comment field of the CRF page and the respective narratives of the SAE
–
–
–
–
–
–
–
•
•
•
Location of perforation, leakage, fistula, abscess
Location/extent of abdominal tumour manifestations,
Imaging & reports (CT, ultrasound, endoscopy, pathology, etc.)
Prior surgery (location, wound healing complications)
Concomitant diseases with GI involvement (eg, Crohn’s, vasculitis, tuberculosis, diverticulitis)
Thromboembolic events (or predisposition)
At least two elevated liver enzymes within a 2 week period, based on laboratory values
ALT and/or AST >5 x ULN without bilirubin elevation measured in the same blood draw
sample*
ALT and/or AST >2.5 x ULN combined with bilirubin >1.5 x ULN measured in the same blood
sample*
*Where this occurs, patients should be followed up for potential drug-induced liver injury
(DILI), and the DILI Checklist Form(s) completed
NiCCC - Initiation Slides V1.0, 21Jul2014
39
Reporting SAEs and AESIs
•
•
•
•
•
•
•
•
•
•
•
Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) must be
reported immediately (within 24 hours of knowledge of the event)
AESIs only require to be reported for patients randomised to receive Nintedanib
SAEs and AESIs are reported using the CTU SAE report form (and BI SAE report form for
patients receiving Nintedanib)
Sites must complete the SAE report form(s) and fax the report(s) to Pharmacovigilance at the
Glasgow CTU fax number +44 (0)141 301 7213
The CTU will create a SAE reference number and will send an acknowledgement fax to
confirm receipt (no reference number will be generated for AESIs)
The CTU will request additional information if the SAE is unexpected
CTU will raise queries for any inconsistent or missing information (but not for AESIs)
If the AESI is a potential drug-induced liver injury (DILI), the DILI Checklist Form(s) must also
be completed and submitted to Pharmacovigilance at the Glasgow CTU fax number 0141 301
7213
SAEs must be reported locally by the PI at each site in accordance with the local practice at
their site (i.e. R&D Office)
SAEs and AESIs are required to be reported for up to 30 days after discontinuation of trial
medication
Any SAE that occurs after 30 days post treatment is also required to be reported if the PI
thinks that the SAE is related to the protocol treatment, and is medically important
NiCCC - Initiation Slides V1.0, 21Jul2014
40
Reporting Potential DILIs
•
•
•
•
•
•
•
•
•
•
•
•
A DILI is a particular criteria of Adverse Event of Special Interest (AESI) that requires additional reporting
for patients receiving Nintedanib. Not all AESIs will be DILIs
DILIs must be reported immediately (within 24 hours of knowledge of the event)
DILIs are reported using the CTU SAE report form, BI SAE report form and the DILI Checklist Form(s)
Sites must complete the SAE report form and fax the report to Pharmacovigilance at the Glasgow CTU fax
number +44 (0)141 301 7213
The CTU will send an acknowledgement fax to confirm receipt (no reference number will be generated for
DILIs)
The CTU will may request additional information on the SAE report form
CTU will raise queries for any inconsistent or missing information on the SAE report form, only if the DILI
event also meets the criteria for being a SAE
DILI Checklist Forms
If the AESI is a potential drug-induced liver injury (DILI), the DILI Checklist Form(s) should also be
completed and these should be submitted to the CRUK CTU Trials Unit , Fax no: ++ 44 141 301 7213
The DILI Checklist Form(s) will be forwarded by the CRUK CTU Trials Unit to Boehringer Ingelheim
Pharmacovigilance Department
Boehringer Ingelheim Pharmacovigilance may request additional information on the DILI Checklist Form
directly with sites
Boehringer Ingelheim Pharmacovigilance will raise queries for any inconsistent or missing information on
the DILI Checklist form directly with sites
NiCCC - Initiation Slides V1.0, 21Jul2014
41
Procedure for Reporting SAEs and SAE Report Processing
Data Flow For SAE Reports
CTU
generates
Patient
SAE and DCF
SAE
queries
form
completed
Site
complete
Patient
SAE andSAE
SAE
report
form(s)
form completed
CTU
faxes
DCFs
to site/
Patient
SAE
and SAE
form
Centre (for faxing
to country site)
completed
Fax +44 0141 301 7213
Site/
Country
Centre
fax
Patient
SAE and
SAE form
SAE report(s)
to CTU fax
completed
(+44) 0141 301 7213
Site
resolves
queries
Patient
SAE and
SAE
within
2 weeks
form completed
CTU
faxSAE
SAE
report
Patient
and
SAE
acknowledgment
form completed
receipt to site/centre
Site queries to be signed
Patient SAE and SAE form
by Principal Investigator
completed
or delegated doctor
CTU generate SAE
Patient SAE and SAE form
reference number (not for
completed
AESIs)
Yes
CTU
dataSAE
entry
SAE
Patient
andofSAE
report
(
not for AESIs)
form completed
onto trial database
Is SAE
CTUrelated
to IMA?
DCF queries
required?
No
CTU
DataSAE
checked
final
Patient
and SAE
dataform
check
generated
completed
CTU
editSAE
check
SAE
Patient
andofSAE
report
data
(Not AESIs)
form
completed
CTU
queries
entered
Patient
SAE and
SAE
onto
trialcompleted
database
form
CTU checks
SAE
Patient
SAE and
SAE
report
data
form completed
NiCCC - Initiation Slides V1.0, 21Jul2014
SAE Data Flow Version 3 31 Mar 2014
Site
faxes
DCFs
CTU
Patient
SAE
and to
SAE
form
or to Centre (for
faxing to CTU)
completed
Fax +44 0141 301 7213
42
Procedure for Identifying Suspected Unexpected Serious
Adverse Reactions (SUSARs)
• A checklist will be used to identify SUSARs that require expedited
reporting to the Regulatory Authority, Main REC and Sponsor
• The checklist is a list of the events expected to occur in patients
receiving the protocol treatment (Chemotherapy & Nintedanib) taken
from the section of the Investigator Brochure (IB) and Summary of
product Characteristics (SmPCs) that have regulatory approval when
the SAE is reported. For any SAE that is documented as related to
protocol treatment (SAR) and is not listed on the checklist, the Chief
Investigator (CI) will be contacted for an opinion of SUSAR status
(unexpectedness)
• The CI is responsible for deciding if a SAR requires expedited reporting
• BI will be informed of the decision to report a SAR as a SUSAR and
receive a copy of the SUSAR report
NiCCC - Initiation Slides V1.0, 21Jul2014
43
Expedited Reporting
SAEs that meet the criteria for SUSARs will be reported to the
Regulatory Authority, REC, BI and Sponsor where in the opinion
of the CI the event was:
• Related – that is, resulted from administration of any of the trial drugs
And
• Unexpected – that is the type of event is not listed in the regulatory
approved IB or SmPCs as an expected occurrence
SUSAR reports will be submitted using Eudravigilance within 7 days for
fatal/life threatening events and 15 days for all other events
NiCCC - Initiation Slides V1.0, 21Jul2014
44
Development Safety Update Reports
• A Development Safety Update Report (DSUR) covering the
safety of all trial participants will be prepared by the CRUK,
CTU and submitted annually to the Regulatory Authority in
the UK, REC BI, Sponsor & UK trial Investigators.
• The DSUR will also be submitted to the European
Coordinating Centres for submitting to the Regulatory
Authorities, RECs and Investigators following the
requirements of the countries they are coordinating.
NiCCC - Initiation Slides V1.0, 21Jul2014
45
NiCCC – MONITORING UK SITES (1)
Central Monitoring
• trial sites will be monitored centrally by checking incoming forms for compliance with the
protocol, data consistency, missing data and timing. trial staff will be in regular contact with
site personnel (by phone/fax/email/letter) to check on progress and deal with any queries
that they may have.
On-site and Remote Telephone Monitoring
•
The 1st visit will take the form of a remote telephone monitoring visit when the first patient
at site has completed two cycles of treatment
•
A 2nd telephone monitoring visit will be conducted six months after the randomisation of
the 1st patient at site
•
The time & date will be agreed with a member of the Site trial Team & a separate time &
date agreed with a member of the Clinical Trials Pharmacy Department
•
A pro forma covering the questions which will be covered during the telephone monitoring
visit will be sent with confirmation of the confirmation of the agreed date
•
Please set aside 50 to 70 minutes for this call.
NiCCC - Initiation Slides V1.0, 21Jul2014
46
MONITORING UK SITES (2)
The 3rd visit will take the form of an on site monitoring visit 12 months after randomisation
of the first patient at a site :
•
Investigators and site staff will be notified in advance about forthcoming pre arranged monitoring
visits.
•
All patient source documentation should be made available to enable Source Document Verification
by the Clinical Trial Monitor.
•
A full working day is required for on-site visits & arrangements should be in place to facilitate the
monitor access on the agreed date.
•
If sites are able to provide printed results/reports these must be filed in the source documents.
•
If a site is using electronic data reporting systems or electronic records & hard copies are not available
the clinical trial monitor must be permitted access to the system either by being issued with a
temporary login or a member of staff available for the duration of the visit to facilitate electronic
access to authorised reports/results.
•
The pharmacy department responsible for the trial will be visited to allow monitoring of the pharmacy
site file and review of security, storage and accountability of trial drugs.
•
All findings will be discussed at an end of visit and any unresolved issues raised as Action Points.
•
Action Points will be followed up by the monitor until resolved.
NiCCC - Initiation Slides V1.0, 21Jul2014
47
Investigator Responsibilities
The following principles are from ICH GCP Topic E6 and apply to clinical trials of
Investigational Medicinal Products:
•
Qualifications & Agreements:
-The Investigator should be qualified by education, training & experience.
-Thoroughly familiar with protocol & medicinal products.
-Comply with GCP and applicable regulations.
-Permit – monitoring and audit by the sponsor and inspection by regulatory authorities.
-Maintain a delegation logs of staff involved in the clinical trial at the trial site.
-Ensure that all persons assisting with the trial are adequately informed about the protocol,
IMP and their duties and functions.
•
Resources:
-The Investigator should have sufficient time to properly conduct and complete the trial
within the agreed period.
-Have available adequate facilities and qualified staff to conduct the trial properly and safely.
NiCCC - Initiation Slides V1.0, 21Jul2014
48
Investigator Responsibilities
•
•
•
Medical Care of Trial Subjects:
A qualified physician who is an Investigator (or co-investigator) should be responsible
for all trial related medical decisions.
During and following participation the Investigator should ensure adequate medical
care for any adverse events (AEs).
The Investigator should make as reasonable effort to ascertain reasons for withdrawal
from the trial (although a subject is not obliged to give reasons)
Ethics:
Before initiating the trial there should be written and dated approval/favourable
opinion from the Ethics Committee for the protocol, patient information
sheet/consent form and any amendments.
Compliance with Protocol:
The Investigator should conduct the trial in compliance with the protocol.
Not implement any deviation from the protocol without prior approval/favourable
opinion of the IEC and the sponsor.
The Investigator should document and explain any deviation from the protocol.
NiCCC - Initiation Slides V1.0, 21Jul2014
49
Investigator Responsibilities
•
The IMP :
Investigator has responsibility for IMP accountability at trial site
Some/all IMP duties at the trial site may be assigned to suitably qualified pharmacist.
Records must be maintained: delivery, inventory, use and destruction
Storage of the IMP should be as specified by the sponsor/regulatory requirements.
The IMP should only be used in accordance with the protocol.
The Investigator (or designee) should explain the correct use of the IMP to each patient.
•
Registration & Randomisation:
The Investigator should follow the trial’s registration and randomisation procedures as detailed in
the protocol.
•
Informed consent:
In obtaining and documenting informed consent, the investigator should comply with the
applicable regulatory requirement (s), and should adhere to GCP and to the ethical principles that
have their origin in the Declaration of Helsinki.
NiCCC - Initiation Slides V1.0, 21Jul2014
50
Investigator Responsibilities
•
Reports & records
–
The investigator is responsible for accuracy, completeness, legibility and timeliness of
the data reported to the sponsor.
Data reported on CRFS, from source documents should be consistent with source
documents or discrepancies explained.
Corrections should be : dated, initialled, explained (if necessary) and should not
obscure the original entry.
All trial documents should be maintained as specified in ICH GCP E6, Section 8
(Essential documents for the conduct of a clinical trial).
•
Safety reporting:
Investigators must report Serious Adverse Events to the sponsor as soon as they
become aware of the event.
NiCCC - Initiation Slides V1.0, 21Jul2014
51
Other Site Staff
The Principal Investigator has overall responsibility for the conduct of the clinical trial
at the trial site.
BUT
•
•
•
•
All staff must comply with GCP.
Staff should only perform tasks delegated to them.
Staff should ensure that their details are available to the Investigator.
Staff should maintain appropriate confidentiality at all times
NiCCC - Initiation Slides V1.0, 21Jul2014
52
CONTACT DETAILS FOR CRUK CTU
Project Manager
Claire Lawless
Tel: 0141 301 7947
Fax: 0141 301 7946
E-mail: [email protected]
Clinical Trial Coordinator
Laura Douglas
Tel: 0141 301 7215
Fax: 0141 301 7219
E-mail: [email protected]
Pharmacovigilance Manager
Lindsey Connery
Tel:
0141 301 7209
Fax:
0141 301 7213
E-mail: [email protected]
Pharmacovigilance CTC
Susannah Radford
Tel: 0141 301 7211
Fax: 0141 301 7213
E-mail: [email protected]
Clinical Trial Monitor
Calum Innes
Tel: 0141 301 7948
Fax: 0141 301 7187
Mobile : 07825 030 429
E-mail: [email protected]
Postal Address
Cancer Research UK Clinical Trials Unit
Level 0,
Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow, G12 0YN
NiCCC - Initiation Slides V1.0, 21Jul2014
53