Front-line therapy in CLL: assessment of ibrutinib-containing regimes | Recruiting
Front-line therapy in CLL: assessme... | Recruiting
Front-line therapy in CLL: assessment of ibrutinib-containing regimes
FLAIR

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Medical Conditions
  • Topic: Cancer
  • Subtopic: Haematological Oncology
  • Disease: Leukaemia (chronic)
Primary Contact Details
Mr Jamie Oughton
+44 (0)113 343 1494
See all trial contact details
Recruitment Status
Recruiting
Trial source and source ID number
ISRCTN01844152
This information is designed to help you decide whether this trial is of interest. In some cases it is provided as a link to more detailed patient information or it may still be awaited from the organisation running the trial. Please look again shortly if the information you need is not here or, if named, contact the researcher named above.
Summary
http://www.cancerresearchuk.org/about-cancer/trials/a-trial-ibrutinib-rituximab-chronic-lymphocytic-leukaemia-flair
Research Details
  • Current hypothesis as of 07/09/2018:
    The trial originally aimed to compare the effect on progression-free survival (PFS) of ibrutinib plus rituximab (IR) with that of fludarabine, cyclophosphamide and rituximab (FCR) in patients with previously untreated chronic lymphocytic leukaemia (CLL).

    The amendment to include the additional trial arms will allow a comparison of PFS between ibrutinib plus venetoclax (I+V) and ibrutinib alone (I) with FCR, and a comparison of minimal residual disease (MRD) negativity rates in I+V with those in I.

    Previous hypothesis:
    The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of progression-free survival.
Phase
Not Applicable
Study Design
Randomised; Interventional; Design type: Treatment
Study Type
Interventional
Intervention

Current interventions as of 07/09/2018:
Participants will be randomised on a 1:1:1 basis to receive standard therapy with fludarabine, cyclophosphamide and rituximab (FCR), ibrutinib monotherapy (I) or ibrutinib + venetoclax (I+V).

The IR arm has been closed to recruitment.

Previous interventions as of 29/06/2017:
Participants will be randomised on a 1:1:1:1 basis to receive standard therapy with fludarabine, cyclophosphamide and rituximab (FCR), ibrutinib plus rituximab (IR), ibrutinib monotherapy (I) or ibrutinib + venetoclax (I+V).

Added 24/07/2017:
FCR: fludarabine (oral), cyclophosphamide (oral) and rituximab (intravenous infusion). F (24mg/m2/day) and C (150mg/m2/day) are administered days 1-5 and R is administered at 375mg/ m2 for day 1 cycle 1 and then at 500mg/m2 for day 1 for cycles 2-6. Each cycle is repeated every 28 days and there are 6 cycles.
IR: ibrutinib (oral) and rituximab. 6 cycles of R as per FCR. Ibrutinib (420mg) is administered daily for six years.
I: ibrutinib monotherapy is administered as per IR
I+V: ibrutinib + venetoclax (oral): ibrutinib is administered as per IR. Venetoclax is given daily from week 9 onwards in weekly dose increments (20mg, 50mg, 100mg, 200mg and 400mg) after which 400mg is administered for six years.
Follow up: baseline, 9 months post randomisation then every six months until 7 years or disease progression. All participants will be followed up at least annually until death.

Previous interventions:
Participants will be randomised on a 1:1 basis to receive standard therapy with fludarabine, cyclophosphamide and rituximab (FCR) or ibrutinib plus rituximab (IR).

Intervention Type
Drug
Primary Outcome Measures
    Current primary outcome measure as of 07/09/2018:
    1. Whether I+V is superior to FCR in terms of progression-free survival.
    2. Whether I+V is superior to I in terms of Minimal Residual Disease negativity. The proportion of concurrently randomised participants who are MRD negative in the bone marrow at any time during the trial will be summarised by treatment arm and compared using a binary logistic regression model adjusted for the minimisation factors and trial stage, excluding centre, and Kaplan-Meier curves will be presented. The analysis of MRD negativity will be initially carried out at 2 years after the close of recruitment.

    Previous primary outcome measure:
    The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of progression-free survival, and whether IR toxicity rates are favourable.
Secondary Outcome Measures
    Current secondary outcome measures as of 10/09/2018:
    1. PFS of I+V in comparison with I. This is assessed using time from randomisation to first documented evidence of disease progression (as defined by IWCLL criteria) or death from any cause. Participants who do not progress will be censored at the last date they were known to be alive and progression-free.
    2. PFS of I in comparison with FCR. This is assessed using time from randomisation to first documented evidence of disease progression (as defined by IWCLL criteria) or death from any cause. Participants who do not progress will be censored at the last date they were known to be alive and progression free.
    3. Overall survival. This is assessed using time from randomisation to date of death from any cause. Participants not known to have died will be censored at the date they were last known to be alive.
    4. Proportion of participants obtaining undetectable MRD, as defined by IWCLL criteria. A negative MRD is defined as the presence of <0.01% CLL cells in the bone marrow. Achievement of MRD negativity is defined as a MRD negative results at any time over the length of the trial.
    5. Stopping I-containing therapy in MRD negative patients. Participants receiving I, IR or I+V who achieve MRD negativity in the bone marrow will be able to stop treatment. MRD levels will be monitored over time following stopping treatment.
    6. Restarting I-containing therapy on MRD relapse. Those who relapse at the MRD level will restart treatment and will be assessed further for MRD response.
    7. Response to therapy, as defined by IWCLL criteria. For participants randomised to FCR or IR, response is assessed at 3 months post-treatment with FCR or R and again at the end of treatment with ibrutinib for participants randomised to IR. For participants randomised to I or I+V, response is assessed at 9 months post-randomisation and again at the end of treatment.
    8. Safety and toxicity assessed using adverse events reported throughout the trial, as graded by CTCAE V4.03 , and determined by routine clinical assessments at each centre.
    9. Health-related quality of life. The EORTC QLQC30 and EORTC QLQCLL16 will be used to measure participant assessed QoL prior to randomisation, at the end of treatment with FCR and R (for participants randomised to FCR or IR) or at 6 months post-randomisation (for participants randomised to I or I+V), and then at 6-monthly visits.
    10. Cost-effectiveness. The SF12 and EQ5D will be used to produce quality adjusted life years (QALYs). NHS resource use and participants’ out of pocket expenses will be collected via the Case Record Forms, as well as health economics patient questionnaires. These will be collected prior to randomisation, at the end of treatment with FCR and R (for participants randomised to FCR or IR) or at 6 months post-randomisation (for participants randomised to I or I+V), and then at 6-monthly visits.

    Previous secondary outcome measures as of 07/09/2018:
    1. PFS of I+V in comparison with I
    2. PFS of I in comparison with FCR
    3. Overall survival
    4. Proportion of participants obtaining undetectable MRD, as defined by IWCLL criteria
    5. Stopping of I-containing therapy in MRD-negative patients. Participants who have an MRD negative result in the peripheral blood at any timepoint between 12 and 30 months post-randomisation will be eligible to stop treatment prior to the 6 years post-randomisation timepoint if they confirm MRD negativity in the bone marrow.
    6. Time to MRD relapse for participants who stop I-containing treatment based on MRD negativity and then go on to relapse at the MRD
    7. Response to therapy, as defined by IWCLL criteria. For each comparison, the best response for each participant at either 3 months post-treatment with FCR, 9 months post randomisation (for participants randomised to I or I+V) or the end of treatment (for I or I+V) will be summarised by treatment group and overall. The proportion of participants achieving a Complete Response (CR+CRi) and an Overall Response (at least a PR) at any stage during the trial will be summarised by treatment arm
    8. Safety and toxicity. Safety analyses will summarise the AR, SAE, SAR and SUSAR rates per participant, by treatment received and overall for all participants randomised to stages II and III. ARs will be presented by CTCAE toxicity grade (V4.0.3).
    9. Health-related quality of life assessed using all domains of the EORTC QLQ-C30 and the CLL-specific module, EORTC QLQ-CLL16.
    10. Cost-effectiveness

    Previous secondary outcome measures:
    1. Overall survival
    2. Undetectable minimal residual disease
    3. Response to therapy
    4. Health-related quality of life
    5. Cost-effectiveness
Publication(s)
2017 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/28830517
Result Reports
Sorry, this information is not available
This information is designed to help you decide whether this trial is of interest. In some cases it is provided as a link to more detailed patient information or it may still be awaited from the organisation running the trial. Please look again shortly if the information you need is not here or, if named, contact the researcher named above.
Gender
Both
Age Range
Adult
Who Can Participate
Patient
Number of Participants
Planned Sample Size: 1576; UK Sample Size: 1576
Participant Inclusion Criteria
    1. At least 18 years old. Maximum age of 75 years old.
    2. B-CLL with a characteristic immunophenotype, including small lymphocytic lymphoma
    3. Binet’s Stages C, B or Progressive Stage A
    4. Requiring therapy by the IWCLL criteria in that they must have at least one of the following:
    4.1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia.
    4.2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly
    4.3. Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
    4.4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months as long as the lymphocyte count is over 30 x 10^9/L
    4.5. A minimum of any one of the following disease-related symptoms must be present:
    4.5.1. Unintentional weight loss more than or equal to 10% within the previous 6 months.
    4.5.2. Significant fatigue (i.e. Eastern Cooperative Oncology Group PS 2 or worse; cannot work or unable to perform usual activities)
    4.5.3. Fevers of greater than 38.0°C for 2 or more weeks without other evidence of infection
    4.5.4. Night sweats for more than 1 month without evidence of infection
    5. Considered fit for treatment with FCR as determined by the treating clinician
    6. World Health Organisation (WHO) performance status (PS) of 0, 1 or 2
    7. Able to provide written informed consent
    8. Biochemical values must be within the following limits within 14 days prior to randomization and at baseline:
    8.1. Alanine aminotransferase (ALT) 3 x upper limit of normal (ULN). Aspartate aminotransferase (AST) 3 x ULN.
    8.2. Total bilirubin = 1.5 x ULN, unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin
Participant Exclusion Criteria
    Current exclusion criteria as of 07/09/2018:
    1. Prior therapy for CLL
    2. History or current evidence of Richter’s transformation
    3. Major surgery within 4 weeks prior to randomisation
    4. Active infection
    5. Above 20% P53 deletion, determined by FISH
    6. Past history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies
    7. Concomitant warfarin or equivalent vitamin K inhibitor - added 29/06/2017: or other oral anticoagulant treatment; anyone requiring anticoagulation treatment for greater than 6 months is not eligible for trial entry
    8. Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 30 days after treatment with ibrutinib has finished, whichever is latest. Women must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction
    9. Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 3 months after treatment with ibrutinib has finished, whichever is latest, unless they are surgically sterile
    10. CNS involvement with CLL
    11. Symptomatic cardiac failure not controlled by therapy, or unstable angina not adequately controlled by current therapy (in patients with a significant cardiac history the left ventricular function should be assessed and patients with severe impairment should be excluded)
    12. Respiratory impairment (bronchiectasis or moderate COPD)
    13. Other severe, concurrent diseases or mental disorders that could interfere with their ability to participate in the study
    14. Inability to swallow oral medication
    15. Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease etc)
    16. Known HIV positive
    17. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded
    18. Positive serology for Hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result
    19. History of prior malignancy, with the exception of the following:
    19.1. Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician
    19.2. Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
    19.3. Adequately treated cervical carcinoma in situ without current evidence of disease
    20. Persisting severe pancytopenia (neutrophils <0.5 x 10^9/l or platelets <50 x 10^9/l) unless due to direct marrow infiltration by CLL
    21. Current treatment with prednisolone of >10 mg/day
    22. Active haemolysis (patients with haemolysis controlled with prednisolone at a dose 10 mg or less per day can be entered into the trial)
    23. Patients with a creatinine clearance of less than 30 ml/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula)
    24. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
    25. Requirement for treatment with a strong CYP3A4/5 inhibitor or inducer
    26. Cardiac event (eg. recent myocardial infarction, coronary artery stent) requiring dual antiplatelet treatment.
    27. Allergy or inability to tolerate uric acid reducing agents (eg allopurinol/rasburicase).
    28. Unwilling or unable to take PCP prophylaxis (eg cotrimoxazole).

    Previous exclusion criteria:
    1. Prior therapy for CLL
    2. History or current evidence of Richter’s transformation
    3. Major surgery within 4 weeks prior to randomisation
    4. Active infection
    5. Above 20% P53 deletion, determined by FISH
    6. Past history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies
    7. Concomitant warfarin or equivalent vitamin K inhibitor - added 29/06/2017: or other oral anticoagulant treatment; anyone requiring anticoagulation treatment for greater than 6 months is not eligible for trial entry
    8. Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 30 days after treatment with ibrutinib has finished, whichever is latest. Women must agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction
    9. Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception whilst receiving treatment and for 12 months after treatment with rituximab has finished, or 3 months after treatment with ibrutinib has finished, whichever is latest, unless they are surgically sterile
    10. CNS involvement with CLL
    11. Symptomatic cardiac failure not controlled by therapy, or unstable angina not adequately controlled by current therapy (in patients with a significant cardiac history the left ventricular function should be assessed and patients with severe impairment should be excluded)
    12. Respiratory impairment (bronchiectasis or moderate COPD)
    13. Other severe, concurrent diseases or mental disorders that could interfere with their ability to participate in the study
    14. Inability to swallow oral medication
    15. Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease etc)
    16. Known HIV positive
    17. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded
    18. Positive serology for Hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result
    19. History of prior malignancy, with the exception of the following:
    19.1. Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years prior to screening and felt to be at low risk for recurrence by treating physician
    19.2. Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma without current evidence of disease
    19.3. Adequately treated cervical carcinoma in situ without current evidence of disease
    20. Persisting severe pancytopenia (neutrophils <0.5 x 10^9/l or platelets <50 x 10^9/l) unless due to direct marrow infiltration by CLL
    21. Current treatment with prednisolone of >10 mg/day
    22. Active haemolysis (patients with haemolysis controlled with prednisolone at a dose 10 mg or less per day can be entered into the trial)
    23. Patients with a creatinine clearance of less than 30 ml/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula)
    24. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
    25. Requirement for treatment with a strong CYP3A4/5 inhibitor or inducer
This information is designed to help you decide whether this trial is of interest. In some cases it is provided as a link to more detailed patient information or it may still be awaited from the organisation running the trial. Please look again shortly if the information you need is not here or, if named, contact the researcher named above.
Trial Location(s)
Bristol
Avon
BS2 8ED
Sketty
Carmarthenshire
SA2 8QA
London
Greater London
SW3 6JJ
Manchester
Greater Manchester
M20 4BX
Southampton
Hampshire
SO16 6YD
Wythenshawe
M23 9LT
Glasgow
Lanarkshire
G12 0YN
Blackpool
FY3 8NR
Leeds
LS9 7TF
London
SW17 0QT
London
NW1 2BU
London
SE5 9RS
Poole
BH15 2JB
Romford
RM7 0AG
Sheffield
S10 2JF
Watford
WD18 0HB
Cardiff
CF14 4XW
Paisley
PA2 9PN
Chester
CH2 1UL
Cambridge
CB2 0QQ
Birmingham
B15 2TH
Edinburgh
EH4 2XU
Sutton
SM5 1AA
Bordesley Green
B9 5SS
Grimsby
DN33 2BA
Oxford
Oxfordshire
OX3 7LE
London
England
EC1A 7BE
Ipswich
IP4 5PD
Carmarthen
SA31 2AF
Derby
DE22 3NE
Craigavon
Northern Ireland
BT63 5QQ
Bath
BA1 3NG
Bournemouth
BH7 7DW
Peterborough
PE3 9GZ
Mile End
CO4 5JL
Worcester
WR5 1DD
Cheltenham
GL53 7AN
Taunton
TA1 5DA
York
YO31 8HE
Aberdeen
AB25 2ZN
Stoke-on-Trent
ST4 6QG
Belfast
BT9 7AB
Coventry
CV2 2DX
Orpington
BR6 8ND
Great Yarmouth
NR31 6LA
Dudley
DY1 2HQ
Doncaster
DN2 5LT
Basildon
SS16 5NL
Scunthorpe
DN15 7BH
Lancaster
LA1 4RP
West Bromwich
B71 4HJ
Cottingham
HU16 5JQ
Oldham
Lancashire
OL1 2JH
Basingstoke
RG24 9NA
Middlesbrough
North Yorkshire
TS4 3BW
Plymouth
PL6 8DH
Nottingham
Nottinghamshire
NG5 1PB
Manchester
M13 9WL
Portsmouth
PO6 3LY
Gloucester
GL1 3NN
Worthing
BN11 2DH
Wrexham
LL13 7TD
Nuneaton
CV10 7DJ
Newport
NP20 2UB
Bradford
BD9 6RJ
Liverpool
L9 7AL
Exeter
EX2 5DW
Guildford
GU2 7XX
Liverpool
L7 8XP
Redhill
RH1 5RH
Rotherham
S60 2UD
Leicester
LE5 4PW
Thornton Heath
CR7 7YE
Salford
M6 8HD
Glasgow
G42 9LF
Aylesbury
HP21 8AL
Truro
Cornwall
TR1 3LJ
London
W12 0HS
Sutton Coldfield
B75 7RR
Halifax
HX3 0PW
Londonderry
BT47 6SB
Northampton
NN1 5BD
Sutton-in-Ashfield
NG17 4JL
Huddersfield
HD3 3EA
Torquay
Devon
TQ2 7AA
Epsom
KT18 7EG
Gateshead
NE9 6SX
Leeds
LS2 9JT
Abergavenny
NP7 7EG
Kirkcaldy
KY2 5AH
Inverness
IV2 3UJ
Harrogate
HG2 7SX
Barnet
EN5 3DJ
Eaglestone
Buckinghamshire
MK6 5LD
Isleworth
Middlesex
TW7 6AF
Rhyl
LL18 5UJ
Chichester
PO19 6SE
Winchester
England
SO22 5DG
Grantham
NG31 8DG
Lincoln
LN2 5QY
Airdrie
ML6 0JS
Boston
PE21 9QS
Melrose
TD6 9BS
Dunfermline
Scotland
KY12 0SU
Salisbury
SB2 8BJ
Bangor
LL57 1PW
Trial Contact(s)
Primary Trial Contact
Mr Jamie Oughton
+44 (0)113 343 1494
Other Trial Contacts
Sorry, this information is not available
Countries Recruiting
United Kingdom
This information is designed to help you decide whether this trial is of interest. In some cases it is provided as a link to more detailed patient information or it may still be awaited from the organisation running the trial. Please look again shortly if the information you need is not here or, if named, contact the researcher named above.
Scientific Title
FLAIR: Front-Line therapy in CLL: Assessment of Ibrutinib-containing Regimes: a randomised controlled trial
EudraCT Number
2013-001944-76
Funder(s)
  • Cancer Research UK
  • Grant Codes: C18027/A15790
  • Janssen Pharmaceuticals
  • AbbVie Ltd
Other Study ID Numbers
16675
Sponsor(s)
University of Leeds (UK)
Key Dates

Recruitment Start Date

01 Sep 2014

Recruitment End Date

01 Jan 2020

Trial Start Date

01 Aug 2014

Trial End Date

01 Jan 2030

Date added to source

08 Aug 2014

Date updated in source

10 Sep 2018