Condition category
Cancer
Date applied
08/08/2014
Date assigned
08/08/2014
Last edited
19/10/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Scientific

Primary contact

Mr Jamie Oughton

ORCID ID

Contact details

Clinical Trials Research Unit (CTRU)
Woodhouse Lane
Leeds
LS2 9JT
United Kingdom
+44 (0)113 343 1494
j.oughton@leeds.ac.uk

Additional identifiers

EudraCT number

2013-001944-76

ClinicalTrials.gov number

Protocol/serial number

16675

Study information

Scientific title

FLAIR: Front-Line therapy in CLL: Assessment of Ibrutinib-containing Regimes: a randomised controlled trial

Acronym

FLAIR

Study 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.

Ethics approval

NRES Committee Yorkshire & The Humber - Leeds West, 17/06/2014, ref: 14/YH/0085

Study design

Randomised; Interventional; Design type: Treatment

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Topic: Cancer; Subtopic: Haematological Oncology; Disease: Leukaemia (chronic)

Intervention

Current 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

Phase

Not Applicable

Drug names

Fludarabine, cyclophosphamide, rituximab, ibrutinib, venetoclax

Primary outcome measures

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

1. Overall survival
2. Undetectable minimal residual disease
3. Response to therapy
4. Health-related quality of life
5. Cost-effectiveness

Overall trial start date

01/08/2014

Overall trial end date

01/01/2030

Reason abandoned

Eligibility

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 type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 1576; UK Sample Size: 1576

Participant 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

Recruitment start date

01/09/2014

Recruitment end date

01/01/2020

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Clinical Trials Research Unit (CTRU)
Leeds
LS2 9JT
United Kingdom

Trial participating centre

87 other centres
-

Sponsor information

Organisation

University of Leeds (UK)

Sponsor details

Clinical Trials Research Unit
Leeds Institute of Clinical Trials Research
Leeds
LS2 9JT
United Kingdom

Sponsor type

University/education

Website

Funders

Funder type

Charity

Funder name

Cancer Research UK; Grant Codes: C18027/A15790

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

Janssen Pharmaceuticals

Alternative name(s)

Janssen Pharmaceuticals, Inc.

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United States of America

Funder name

AbbVie Ltd

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal in 2024.

IPD sharing statement
The current data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

31/12/2024

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

2017 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/28830517

Publication citations

Additional files

Editorial Notes

19/10/2017: Publication reference added. 24/07/2017: Publication and dissemination plan added. 29/06/2017: The following changes were made to the trial record: 1. The title was changed from 'Front-Line therapy in CLL: Assessment of Ibrutinib + Rituximab' to 'Front-Line therapy in CLL: Assessment of Ibrutinib-containing Regimes'. 2. The overall trial end date was changed from 01/08/2018 to 01/01/2030. 3. The target number of participants was changed from 754 to 1576. 4. The recruitment end date was changed from 01/08/2018 to 01/01/2020. 5. AbbVie Ltd was added as a funder. 18/10/2016: The recruitment start date was changed from 01/08/2014 to 01/09/2014.