Attenuated dose rituximab with chemotherapy in chronic lymphocytic leukaemia (CLL)

ISRCTN	ISRCTN16544962
DOI	https://doi.org/10.1186/ISRCTN16544962
EudraCT/CTIS number	2009-010998-20
Secondary identifying numbers	HTA 07/01/38; Sponsor ref: HM09/8848

Submission date: 17/09/2008
Registration date: 25/09/2008
Last edited: 24/03/2022

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

http://www.cancerhelp.org.uk/trials/a-trial-adding-rituximab-mitoxantrone-to-fludarabine-cyclophosphamide-treat-chronic-lymphocytic-leukaemia

Contact information

Prof Peter Hillmen
Scientific

Department of Haematology
Level 3
Bexley Wing
St James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom

Phone	+44 (0)113 206 8513
Email	peter.hillmen@nhs.net

Study information

Study design	Multi-centre phase II open non-inferiority randomised controlled trial
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 IIB trial in previously untreated patients with chronic lymphocytic leukaemia (CLL) to compare fludarabine, cyclophosphamide and rituximab (FCR) with FC, mitoxantrone and low dose rituximab (FCM-miniR)
Study acronym	ARCTIC
Study hypothesis	This trial aims to establish whether the addition of mitoxantrone (M) with a reduced dose of rituximab (R), to fludarabine (F) and cyclophosphamide (C) - FCM-miniR is as effective as FCR in terms of response in patients with previously untreated chronic lymphocytic leukaemia (CLL).
Ethics approval(s)	Leeds (East) Research Ethics Committee, 25/06/2009, ref: 09/H1306/54
Condition	Chronic lymphocytic leukaemia (CLL)
Intervention	Patients will be randomised to receive 6 cycles of either FCR or FCM-miniR according to the following regimens: Fludarabine, cyclophosphamide and rituximab (FCR): Fludarabine (oral)* 24 mg/m^2/day, Days 1 to 5 Cyclophosphamide (oral)* 150 mg/m^2/day, Days 1 to 5 Rituximab (intravenous) 375 mg/m^2, Day 1 (Cycle 1) Rituximab (intravenous) 500 mg/m^2, Day 1 (Cycle 2-6) Cycles of FCR are repeated every 28 days for a total of 6 cycles. G-CSF (lenograstim 263 mg/day) for days 7 to 13 is recommended for all subsequent cycles in patients who have to have a previous dose delay due to neutropenia. Patients should be questioned regarding nausea and vomiting or diarrhoea occurring with the prior cycle of therapy and if this is present then the fludarabine and cyclophosphamide should be given via the intravenous route due to concerns over drug absorption. Intravenous fludarabine (25 mg/m^2/day for 3 days) and cyclophosphamide (250mg/m2/day for 3 days) regimens are recommended if the oral regimen is not tolerated. Fludarabine, cyclophosphamide, rituximab and mitoxantrone (FCM-miniR): Fludarabine (oral) 24 mg/m^2/day, Days 1 to 5 Cyclophosphamide (oral)* 150 mg/m^2/day, Days 1 to 5 Mitoxantrone (intravenous) 6 mg/m^2/day, Day 1 Mini Rituximab (intravenous) 100 mg, Day 1 Cycles of FCM-miniR are repeated every 28 days for a total of 6 cycles. G-CSF (lenograstim 263 mg/day) for days 7 to 13 is recommended for all subsequent cycles in patients who have to have a previous dose delay due to neutropenia. *Patients should be questioned regarding nausea and vomiting or diarrhoea occurring with the prior cycle of therapy and if this is present then the fludarabine and cyclophosphamide should be given via the intravenous route due to concerns over drug absorption. Intravenous fludarabine (25 mg/m^2/day for 3 days) and cyclophosphamide (250 mg/m^2/day for 3 days) regimens are recommended if the oral regimen is not tolerated. Patients will be evaluated every 6 months after the end of therapy until disease progression requiring therapy or until 2 years post-randomisation. All patients will be followed-up for survival until death as part of a long term follow-up registry which is currently in set-up.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Mitoxantrone, rituximab, fludarabine, cyclophosphamide
Primary outcome measure	Proportion of patients achieving a complete response (CR), as defined by the IWCLL criteria. A formal assessment of response by IWCLL criteria will be made 3 months after the end of therapy.
Secondary outcome measures	1. Proportion of patients with undetectable minimal residual disease (MRD) according to the IWCLL Response Criteria, assessed at baseline and 3 months after the end of therapy. Patients who are MRD negative at the end of treatment will also be followed up every 6 months after the end of therapy until disease progression requiring therapy or 2 years post-randomisation. All patients will be followed up for survival until death. 2. Overall response rate defined as complete or partial remission by IWCLL Criteria at 3 months after the end of therapy 3. Progression-free survival at 2 years 4. Overall survival at 2 years 5. Safety and toxicity. Adverse events (AEs) related to the treatment will be collected from randomisation until 30 days after the last dose of treatment with FCR or FCM-miniR. 6. Economic evaluation (time frame not yet finalised)
Overall study start date	01/01/2009
Overall study end date	31/12/2011

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	206
Participant inclusion criteria	1. Both males and females, at least 18 years old 2. B-CLL with a characteristic immunophenotype 3. Binet's Stages B, C or Progressive Stage A 4. Requiring therapy by the International Workshop on CLL (IWCLL) criteria in that they must have at least one of the following: Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia 5. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly 6. Massive nodes (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy 7. 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 8. A minimum of any one of the following disease-related symptoms must be present: 8.1. Unintentional weight loss more than or equal to 10% within the previous 6 months 8.2. Significant fatigue (i.e. Eastern Cooperative Oncology Group PS 2 or worse; cannot work or unable to perform usual activities) 8.3. Fevers of greater than 38.0°C for 2 or more weeks without other evidence of infection 8.4. Night sweats for more than 1 month without evidence of infection 9. No prior therapy for CLL 10. World Health Organization (WHO) performance status (PS) of 0, 1 or 2 11. Able to provide written informed consent
Participant exclusion criteria	1. Prior therapy for CLL 2. Active infection 3. Past history of anaphylaxis following exposure to rat or mouse derived CDR-grafted humanised monoclonal antibodies 4. Pregnancy, lactation or women of child-bearing potential unwilling to use medically approved contraception whilst receiving treatment 5. Men whose partners are capable of having children but who are not willing to use appropriate medically approved contraception during the study, unless they are surgically sterile 6. Central nervous system (CNS) involvement with CLL 7. Mantle cell lymphoma 8. Other severe, concurrent diseases or mental disorders 9. Known HIV positive 10. Patient has active or prior hepatitis B or C 11. Active secondary malignancy excluding basal cell carcinoma 12. Persisting severe pancytopenia (neutrophils <0.5 x 10^9/l or platelets <50 x 10^9/l) or transfusion dependent anaemia unless due to direct marrow infiltration by CLL 13. Active haemolysis (patients with haemolysis controlled with prednisolone at a dose 10 mg or less per day can be entered into the trial) 14. Patients with a creatinine clearance of less than 30 ml/min (either measured or derived by the Cockcroft formula)
Recruitment start date	01/01/2009
Recruitment end date	31/12/2011

Locations

Countries of recruitment

England
Ireland
United Kingdom

Study participating centre

St James's University Hospital

Leeds
LS9 7TF
United Kingdom

Sponsor information

Leeds Teaching Hospitals NHS Trust (UK)
Hospital/treatment centre

Research & Development
Floor A/B - Old Site
Leeds General Infirmary
Great George Street
Leeds
LS1 3EX
England
United Kingdom

Phone	+44 (0)113 39 20152
Email	derek.norfolk@leedsth.nhs.uk
Website	http://www.leedsteachinghospitals.com
"ROR"	https://ror.org/00v4dac24

Funders

Funder type

Government

Health Technology Assessment Programme
Government organisation / National government

Alternative name(s): NIHR Health Technology Assessment Programme, HTA
Location: United Kingdom

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan	Not provided at time of registration

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/05/2017		Yes	No
Results article	results	01/11/2017		Yes	No
Plain English results			24/03/2022	No	Yes
HRA research summary			28/06/2023	No	No

Editorial Notes

24/03/2022: Plain English results added.
26/06/2017: Publication references added.
20/02/2009: The public title has been added.
19/02/2009: The target number of participants was changed from 200 to 206.
11/05/2009: The overall trial start and end dates have been changed from 01/03/2009 and 01/05/2011 to 01/01/2009 and 31/12/2011, respectively.