A study comparing intermittent with continuous treatment with ibrutinib in chronic lymphocytic leukaemia (CLL)
| ISRCTN | ISRCTN51675454 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN51675454 |
| EudraCT/CTIS number | 2021-005854-27 |
| IRAS number | 1003615 |
| Secondary identifying numbers | HM21/142069, IRAS 1003615, CPMS 52879 |
- Submission date
- 21/06/2022
- Registration date
- 27/06/2022
- Last edited
- 07/11/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English Summary
https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-ibrutinib-with-and-without-treatment-breaks-for-chronic-lymphocytic-leukaemia-static
Background and study aims
Ibrutinib is one of a group of drugs for chronic lymphocytic leukaemia (CLL) called targeted drugs. Targeted drugs, including ibrutinib, have fewer side effects than traditional chemotherapy. However, as the drug is usually taken for several years, these side effects can be a burden.
There is some evidence that, if ibrutinib is taken for several years, the CLL is more likely to become resistant to this treatment. STATIC will investigated whether having a break from ibrutinib treatment will work as well as continuing treatment without a break, if whether taking a break from ibrutinib reduces side effects, whether it lowers the risk of CLL becoming resistant to ibrutinib, and whether there is any difference in the overall cost of CLL treatment. We also want to know whether having a break from ibrutinib changes how patients are feeling emotionally.
Who can participate?
830 patients will be enrolled into the STATIC trial. These patients will be made up of patients who have been treated on the NHS with Ibrutinib as their second or subsequent treatment for their CLL as well as those who have been treated in another study called the FLAIR trial.
What does the study involve?
Patients in the randomisation trial will be randomly allocated to have either continuous or intermittent treatment with ibrutinib.
A small number of patients finishing FLAIR will be advised to continue ibrutinib as their CLL is not well controlled enough for them to take part in the randomised trial and they can continue ibrutinib treatment in STATIC without being randomised.
What are the possible benefits and risks of participating?
We hope that participants will be helped by taking part in this study, but we can’t guarantee this. However, the information we get from this study will contribute to medical research and help us to improve future treatments for people who have ibrutinib treatment for their CLL. As we learn more about the effects of taking ibrutinib for longer periods of time, pausing ibrutinib for periods, and how this changes the side effects, this may lead to future changes in treatment for CLL patients.
The STATIC Randomised trial will help to understand whether pausing ibrutinib treatment when CLL is well controlled is as good as continuing ibrutinib without a break. Both the randomised trial and clinical need group will give us information about the effects of taking ibrutinib for a long time as well as the benefits and safety of ibrutinib.
Both participants who are randomised to continuous treatment and who enter the patient need cohort will receive treatment for longer periods than standard care, which may prolong the presence of side effects. Participants will be closely monitored and will attend regular outpatient appointments to monitor this, and the side effects can often be managed by lowering drug dose or taking supportive medication.
Participants randomised to the intermittent treatment may have concerns about pausing treatment. However, treatment will only be paused in the trial when a patient is in a good remission, which may last for some considerable time, and will resume treatment when there are early signs of CLL reappearing.
Where is the study run from?
University of Leeds (UK)
When is the study starting and how long is it expected to run for?
June 2022 to September 2031
Who is funding the study?
National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (UK)
Janssen-Cliag (UK)
Who is the main contact?
Rhiannon Lambkin
static@leeds.ac.uk
Contact information
Scientific
Clinical Trials Research Unit
Leeds Institute of Clinical Trials Research
University of Leeds
Leeds
LS2 9JT
United Kingdom
| Phone | +44 (0)1133432813 |
|---|---|
| STATIC@leeds.ac.uk |
Study information
| Study design | STATIC is designed with multiple pathways, the ‘Randomisation Pathway’ and the ‘Clinical Need Cohort’, which route a participant enters will be determined by their eligibility. Randomisation Trial: A prospective, national, multicentre, open-label, randomised, controlled, 2-arm, parallel-group, non-inferiority, phase III trial to assess whether patients with CLL on long-term treatment with a BTK inhibitor, (including ibrutinib) have similar disease control with an intermittent treatment strategy (experimental arm) compared with standard continuous treatment (control arm). Clinical Need Cohort: A prospective, national, multicentre, open-label, single-arm, non-randomised cohort to assess the safety and overall survival of patients with CLL receiving long-term continuous treatment with ibrutinib. |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | A randomised phase III trial comparing intermittent with continuous treatment strategies in chronic lymphocytic leukaemia (CLL) |
| Study acronym | STATIC |
| Study hypothesis | An intermittent treatment strategy using ibrutinib, will reduce treatment-emergent resistance and thus be at least non-inferior to continuous treatment with regards to time to treatment strategy failure whilst reducing resource impact for the NHS and improving quality of life. |
| Ethics approval(s) | Approved 02/08/2022, North East - York Research Ethics Committee (NHSBT Newcastle Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ, UK; +44 207 104 8079; york.rec@hra.nhs.uk), ref: 22/NE/0097 |
| Condition | Chronic lymphocytic leukaemia (CLL) |
| Intervention | In the randomisation pathway participants will be randomised 1:1 to either intermittent ibrutinib, known as the ‘pausing ibrutinib’ arm, or continuous ibrutinib treatment. Participants randomised to continuous treatment will receive ibrutinib (oral) 420mg per day (or other reduced dose, if that dose has been stable for the past 6 months and there are no unresolved toxicities) until strategy failure, defined as active disease as per 2018 iwCLL criteria, death, or the end of the trial. Participants randomised to the ‘pausing ibrutinib’ arm (intermittent treatment strategy) will pause ibrutinib treatment immediately following randomisation, and restart when the restart criteria are met. When treatment restarts, participants restart ibrutinib treatment at the standard dose (or their previous stable reduced dose) until the treatment pausing criteria are met. The pausing and resuming criteria are assessed locally every 3 months at standard clinic visits. Participants can pause and restart treatment multiple times until treatment strategy failure (defined as active disease per 2018 iwCLL criteria) whilst on treatment, death, or end of the study. In the Clinical Need Cohort all participants will to receive ibrutinib (continuous treatment), either at the recommended starting dose, or the stable reduced dose they were receiving at the end of the FLAIR trial, but will not be randomised. Participants in the Clinical Need Cohort will receive treatment during the trials 6 year recruitment period and for the 3 years of follow up, meaning that participants will be on the trial for between 3-9 years, depending upon when they enter the trial. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Ibrutinib (Imbruvica) |
| Primary outcome measure | Time to treatment strategy failure. Time to treatment strategy failure is defined as the time from randomisation to time of treatment strategy failure. Treatment strategy failure is defined as the first documented instance of active disease that does not respond to treatment, or death from any cause measured using patient records throughout the study |
| Secondary outcome measures | 1. Overall survival will be measured for the randomisation trial as the time from randomisation to the time of death from any cause. In the clinical need cohort this will be calculated as the time from registration to the time of death from any cause. 2. Toxicity and tolerability based on adverse events, as graded by CTCAE V5.0 and determined by routine clinical assessments at each centre. 3. Cost effectiveness is defined as a cost per incremental QALY below £20,000 and/or a positive incremental net monetary benefit. The cost-effectiveness of treatment options will be evaluated with respect to this criteria. 4. Quality of life will be assessed using the patient-reported outcome measures: EORTC-QLQ-C30, EORTC-QLQ-CLL and EQ-5D-5L. This will be measured in the randomisation trial only and will be recorded at baseline and after 3, 6 12, 18, 24, 30, 36 and 48 months of trial treatment. 5. Summative treatment-free Interval is defined as the time to treatment strategy failure, excluding any time spent on treatment. 6. Response to retreatment in intermittent treatment arm will be assessed as a patients response (partial remission (PR), stable disease (SD) or progressive disease (PD) according to the response criteria defined by the standard 2018 iwCLL criteria) between 9 and 12 months after restarting ibrutinib. 7. Time to next treatment is defined as the time from randomisation to the start date of the next line of treatment. For the Clinical Need Cohort, this will be time from registration to the start date of the next line of treatment. 8. Response to next treatment for CLL will be assessed as the best response (PR, SD or PD according to the response criteria defined by the standard 2018 iwCLL criteria) achieved by a participant at any timepoint. 9. Rate of resistance mutation between trial arms will be assessed as the proportion of participants in each arm with a detectable BTK mutation at baseline, 24 months and 48 months for all randomised participants, and at 12, 36 months for those participants in whom a BTK mutation is detected. 10. Evolution of resistant sub-clones will be assessed as the proportion of BTK mutations that are identified over time. It will be assessed at baseline and following 24 and 48 months of trial treatment. If resistant subclones are present, biobank samples collected at 12 and 36 months of trial treatment, will be used to identify the onset of these subclones. |
| Overall study start date | 21/06/2022 |
| Overall study end date | 01/09/2031 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 830 |
| Participant inclusion criteria | Trial Registration Inclusion Criteria: 1. At least 18 years old 2. A diagnosis of chronic lymphocytic leukaemia (CLL) or small lymphocyticlymphoma (SLL) (by 2018 iwCLL criteria) 3. World Health Organisation (WHO) performance status (PS) of 0,1 or 2 4. Biochemical values must be within the following limits within 4 weeks prior to randomisation/or registration for the Clinical Need Cohort and at baseline: 4.1. Alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN) OR Aspartate aminotransferase (AST) ≤3 x ULN. 4.2. Total bilirubin ≤1.5 x ULN, unless bilirubin rise is due to Gilbert’s syndrome or of non hepatic origin 5. Agree to follow the pregnancy prevention plan* 6. Able to provide informed consent *Participants randomised to the pause/resume arm must adhere to this whilst receiving ibrutinib, but will not be required to follow contraceptive measures during the planned treatment breaks Additional inclusion criteria for participants in the Clinical Need Cohort: 1. Meet all of the Registration Inclusion criteria 2. Currently receiving ibrutinib and nearing the end or having completed 6 years of ibrutinib treatment on FLAIR** 3. Have signs of progressive or returning CLL after completing 6 years of ibrutinib treatment within FLAIR, but prior to entry into STATIC Additional inclusion criteria for Front Line participants entering the randomisation trial: 1. Meet all of the Registration Inclusion criteria 2. Currently receiving ibrutinib in FLAIR or having completed 6 years of ibrutinib of ibrutinib in FLAIR** 3. In clinical remission all of the following: 3.1. No palpable lymph nodes; 3.2. No palpable spleen; and 3.3. Lymphocyte count below 5x10^9/L continuously for at least the 12 months before randomisation **Patients should enter STATIC on completion of treatment in FLAIR, with no break in therapy, with the exception of participants who have completed the 6 years of treatment in FLAIR prior to STATIC opening Additional inclusion criteria for Previously Treated participants entering the randomisation trial: 1. Meet all of the registration inclusion criteria 2. Currently receiving ibrutinib for at least the previous 36 months. There is no restriction on maximum duration of treatment prior to enrolment. 3. In clinical remission fulfilling all of the following: 3.1. No palpable lymph nodes; 3.2. No palpable spleen; and 3.3. Lymphocyte count below 5x10^9/L continuously for at least the 12 months before randomisation |
| Participant exclusion criteria | Trial Registration Exclusion Criteria: 1. Pregnant females 2. Known intolerance or hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption. 3. Receipt of live vaccination within 4 weeks prior to registration and for the duration of the study. 4. History or current evidence of Richter’s transformation 5. Major surgery within 4 weeks prior to randomisation/or registration for the Clinical Need Cohort 6. Active infection 7. Concomitant warfarin (or equivalent vitamin K inhibitor) 8. Central nervous system involvement with CLL 9. Cardiac failure; including 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) 10. Respiratory impairment (e.g. bronchiectasis or severe COPD) 11. Other severe, concurrent diseases or mental disorders that could interfere with their ability to participate in the study 12. 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),aHB DNA test will be performed and if positive the patients will be excluded. During treatment, these participants should be monitored and managed to prevent HBV reactivation. 13. Positive serology for Hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a test for hepatitis C RNA (for example HCV RNA PCR). If positive the patients will be excluded. 14. Persisting severe pancytopenia (neutrophils <0.5 x 109/L or platelets <50 x 109/L)unless due to direct marrow infiltration by CLL 15. Current treatment with prednisolone of >20mg/day 16. Uncontrolled Active haemolysis 17. History of stroke or intracranial haemorrhage within 6 months prior to enrolment. 18. Requirement for treatment with a strong CYP3A inhibitor or inducer 19. New treatment with two or more antiplatelet drugs, treatment that has been administered at a stable dose for at least 3 months prior to registration is permissible 20. Current treatment with any concomitant ACE inhibitors Additional exclusion criteria for participants in the Clinical Need Cohort: 1. Meet none of the registration exclusion criteria 2. Active Disease, as per the 2018 iwCLL criteria requiring an alternative therapy. 3. Received treatment other than ibrutinib for CLL since completing FLAIR 4. Be eligible for front-line randomisation 5. Ibrutinib treatment break for toxicity/patient choice for more than 28 days in the last 12 months (added 07/11/2024) Additional exclusion criteria for Front-Line participants entering the randomisation trial: 1. Meet none of the registration exclusion criteria 2. Disease progression (according to 2018 iwCLL criteria) 3. Ibrutinib treatment break for toxicity/patient choice for more than 28 days in last 12 months Additional exclusion criteria for Previously Treated participants entering the randomisation trial: 1. Meet none of the registration exclusion criteria 2. Disease progression (according to 2018 iwCLL criteria) 3. Ibrutinib treatment break for toxicity/patient choice for more than 28 days in last 12 months 4. Any illness,disease or condition,such as active cancer or secondary primary malignancy (SPM),with a prognosis of less than 5 years 5. Patients with a creatinine clearance of less than 30ml/min (either measured or derived by the Cockcroft Gault formula or alternative locally approved formula). |
| Recruitment start date | 13/10/2022 |
| Recruitment end date | 01/09/2028 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
Study participating centres
Leeds
LS9 7TF
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Sutton Coldfield
B75 7RR
United Kingdom
Bordesley Green
Birmingham
B9 5ST
United Kingdom
Blackpool
FY3 8NR
United Kingdom
Bradford
BD9 6RJ
United Kingdom
Castle Road
Cottingham
HU16 5JQ
United Kingdom
Manchester
M20 4BX
United Kingdom
Old Road
Headington
Oxford
OX3 7LE
United Kingdom
Clatterbridge Road
Wirral
CH63 4JY
United Kingdom
Plymouth
PL6 8DH
United Kingdom
Grantham
NG31 8DG
United Kingdom
Middlesbrough
TS4 3BW
United Kingdom
Canterbury
CT1 3NG
United Kingdom
Rothwell Road
Kettering
NN16 8UZ
United Kingdom
De Crespigny Park
Denmark Hill
London
SE5 8AB
United Kingdom
Leicester
LE1 5WW
United Kingdom
Lincoln
LN2 5QY
United Kingdom
Standing Way
Eaglestone
Milton Keynes
MK6 5LD
United Kingdom
Parkfield Drive
Taunton
TA1 5DA
United Kingdom
Wolverhampton
WV10 0QP
United Kingdom
Cliftonville
Northampton
NN1 5BD
United Kingdom
Hucknall Road
Nottingham
NG5 1PB
United Kingdom
Boston
PE21 9QS
United Kingdom
Longfleet Road
Poole
BH15 2JB
United Kingdom
Orpington
BR6 8ND
United Kingdom
Cosham
Portsmouth
PO6 3LY
United Kingdom
Sherriff Hill
Gateshead
NE9 6SX
United Kingdom
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
Romford
RM7 0AG
United Kingdom
Rotherham
S60 2UD
United Kingdom
Bournemouth
BH7 7DW
United Kingdom
Treliske
Truro
TR1 3LJ
United Kingdom
Barrack Road
Exeter
EX2 5DW
United Kingdom
Winchester
SO22 5DG
United Kingdom
Dudley
DY1 2HQ
United Kingdom
Odstock Road
Salisbury
SP2 8BJ
United Kingdom
Westbury-on-trym
Bristol
BS10 5NB
United Kingdom
London
EC1A 7BE
United Kingdom
117 Suttons Lane
Hornchurch
RM12 6RS
United Kingdom
Aylesbury
HP21 8AL
United Kingdom
Newton Road
Torquay
TQ2 7AA
United Kingdom
London
NW1 2PG
United Kingdom
Kilmarnock
KA2 0BE
United Kingdom
Airdrie
ML6 0JS
United Kingdom
Cardiff
CF14 4XW
United Kingdom
Isleworth
TW7 6AF
United Kingdom
Worcester
WR5 1ZL
United Kingdom
York
YO31 8HE
United Kingdom
Sponsor information
University/education
UoL / LTHT Joint Sponsor QA Office
Secretariat
University of Leeds
Woodhouse Lane
Leeds
LS2 9JT
England
United Kingdom
| ltht.researchoffice@nhs.net | |
| Website | http://www.leeds.ac.uk/ |
"ROR" |
https://ror.org/024mrxd33 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Health Technology Assessment Programme, HTA
- Location
- United Kingdom
No information available
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/09/2032 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Data from this study will be published once trial end points have been reached and after the overall trial end date. Publication will be via peer reviewed journals as well as via presentations at conferences. A summary of the study results and trial updates will also be shared with participants via the trial sites, patient forums, seminars and digital platforms , once the results have been published. |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
07/11/2024: The following changes were made to the study record:
1. Study website added.
2. Aberdeen Royal Infirmary, Good Hope Hospital, Heartlands Hospital, Blackpool Victoria Hospital, Bradford Royal Infirmary, Castle Hill Hospital, Christie Hospital, Churchill Hospital, Clatterbridge Hospital, Derriford Hospital, Grantham and District Hospital, James Cook University Hospital, Kent and Canterbury Hospitals NHS Trust, Kettering General Hospital, King's College Hospital, Leicester Royal Infirmary, Lincoln County Hospital, Milton Keynes General Hospital, Musgrove Park Hospital, New Cross Hospital, Northampton General Hospital, Nottingham University Hospitals NHS Trust - City Campus, Pilgrim Hospital, Poole Hospital, Princess Royal University Hospital, Queen Alexandras Hospital, Gateshead Hospitals NHS Trust, University Hospitals Birmingham NHS Foundation Trust, Queen's Hospital Romford, Rotherham District General Hospital, Royal Bournemouth Hospital, Royal Cornwall Hospitals NHS Trust, Royal Devon University Healthcare NHS Foundation Trust, Royal Hampshire County Hospital (rhch), Russell's Hall Hospital, Salisbury District Hospital, Southmead Hospital, St Bartholomew's Hospital, St George's Hospital, Stoke Mandeville Hospital, Torbay and South Devon NHS Foundation Trust, University College London Hospitals NHS Foundation Trust, University Hospital Crosshouse, Monklands District General Hospital, University Hospital Wales, West Middlesex University Hospital, The Worcestershire Royal Hospital, York Hospital were added to the study participating centres.
3. The exclusion criteria were updated.
17/06/2024: A link to a plain English summary on an external website has been added to the plain English summary.
19/10/2022: The recruitment start date has been changed from 14/10/2022 to 13/10/2022.
21/09/2022: The following changes were made to the trial record:
1. The ethics approval was added.
2. The recruitment start date was changed from 01/09/2022 to 14/10/2022.
04/07/2022: Internal review.
22/06/2022: Trial's existence confirmed by the National Institute for Health and Care Research (NIHR) (UK).
