ARCTIC (FCR Vs FCM-miniR) Version 1.0
Research type
Research Study
Full title
ARCTIC: Attenuated dose Rituximab with ChemoTherapy In CLL. 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).
IRAS ID
9377
Contact name
Sponsor organisation
Leeds Teaching Hospitals NHS Trust
Eudract number
2009-010998-20
ISRCTN Number
ISRCTN16544962
Research summary
Research Summary:
Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia, affecting approximately 5 in every 100,000 people per year in the UK. In CLL the lymphocytes, a type of blood cell, become 'cancerous' and grow out of control. Patients with CLL develop very large glands, high lymphocyte counts in the blood and their bone marrow fails to make normal blood cells; they suffer from infections, severe tiredness, weight loss and sweating. The current treatment for CLL usually involves two different chemotherapy drugsfluarabine and cyclophosphamine or FC for short) given together, every month for 6 months. Although most patients respond to FC, it cannot kill every CLL cell meaning that patients eventually relapse and need further treatment. Most patients who require treatment will eventually die of CLL and so more effective treatments are needed.Rituximab (R) is an antibody which targets CLL and works in a different way from chemotherapy. It seems that adding rituximab to chemotherapy results in more effective CLL cell killing, with more patients responding, and possibly increases the time until further treatment is required. However, evidence suggests that'sing a smaller dose of rituximab (mini R for short) may be just as effective as using the full dose usually used. Rituximab is given via a drip and so using a smaller dose would decrease the time the drip takes and may decrease any reactions the patient may have to the drug.Mitoxantrone (M) is a chemotherapy drug and evidence suggests that adding this to FC may also make the treatment more effective. It is therefore believed that treatment with FCM-miniR may be just as effective as treatment with FCR. This trial will recruit patients who have not had any treatment for their disease. It will assess the response of patients who are treated with FCR with the response of those treated with FCM-miniR. If the results of this trial are positive, a larger phase III trial is planned.
Summary of results:
About this trial Chemotherapy and a targeted drug is the usual treatment for chronic lymphocytic leukaemia (CLL). For example, people might have all of the following:
• rituximab (a targeted drug)
• fludarabine and cyclophosphamide (chemotherapy drugs)
People only usually have this combination if they are fairly fit and well.
Earlier trials have shown that adding mitoxantrone might improve treatment for CLL. Mitoxantrone is a type of chemotherapy. It works by blocking an enzyme that cancer cells need to divide. Without this enzyme cancer cells are not able to divide and grow.
Doctors also thought that a low dose of rituximab might work just as well as a standard dose of this drug. Rituximab is a monoclonal antibody, it attaches itself to a protein on the leukaemia cell. This makes it easier for the immune system to find the leukaemia cells and kill them.
In this trial, people had one of the following treatments:
• standard dose rituximab with fludarabine and cyclophosphamide (FCR)
• low dose rituximab with mitoxantrone, fludarabine and cyclophosphamide (FCM-miniR)
The aim of the trial was to find out if using a low dose of rituximab and adding mitoxantrone worked as well as standard FCR treatment. The researchers also wanted to compare the side effects of each treatment.Summary of results
This was a phase 2 trial. It recruited 206 people in the UK. It was randomised trial, so the people taking part were put into 1 of 2 treatment groups by a computer.
• Half of people had fludarabine, cyclophosphamide and standard dose rituximab (FCR).
• Half of people had fludarabine, cyclophosphamide, low dose rituximab and mitoxantrone (FCM-miniR).
During the trial, the researchers looked at how well the treatment was working. They found that standard treatment with FCR was working better than treatment with mitoxantrone and low dose rituximab (FCM-miniR). Because of these results the trial closed early.
Response to treatment
Those who were still having FCM-miniR at the time the trial closed were able to change to FCR if they wanted to. Twenty one people chose to cross over from FCM-miniR to complete their treatment with FCR. These people weren’t included in the final results.
Three months after treatment had finished the researchers carried out a final analysis of the results. They looked at how many people had no sign of CLL (a complete response). This included:
• 68 out of the 100 people (68%) who had FCR
• 39 out of the 79 people (49%) who had FCM-miniR
The researchers concluded that this meant that FCR-miniR is not as good as FCR.Adverse events
The researchers compared the number of adverse events of people in the 2 groups. An adverse event means any medical event that happens to people while taking part in a trial. This includes any side effect thought to be due to the treatment in the trial. And any medical event that might not be due to treatment.
The researchers recorded how many people had at least one serious adverse event. For example:
• an infection that needed immediate hospital treatment
• development of squamous cell skin cancer
• diarrhoea that needed hospital treatment as an in patientThose who had at least one serious adverse event included:
• 46 people in the FCM-miniR group
• 49 people in the FCR groupA higher proportion of people in the FCM-miniR group compared with the FCR group were admitted to hospital for a serious adverse event during the trial.
Survival
The trial team also looked at:
• whose leukaemia came back (relapsed) or started to grow again and when this happened (progression free survival)
• how long people lived for (overall survival)The researchers specifically recorded these figures when people had on average been followed up for about 3 years. They found no significant difference in progression free survival or overall survival between the 2 groups.
Conclusion
The researchers concluded that standard dose rituximab with fludarabine and cyclophosphamide remained the best treatment for people with CLL. They also found that adding mitoxantrone increased the side effects that people had.
They recommended that treatment with low dose rituximab, mitoxantrone, fludarabine and cyclophosphamide should not move into phase 3 clinical trials.Peer reviewed scientific journals: doi: 10.1038/leu.2017.96 Leukemia, doi: 10.3310/hta21280 NIHR Health Technology Assessment, doi: 10.1002/ajh.26483 American Journal of Haematology. Conference presentations: BSH 2014 (poster), EHA 2014 (poster), EHA 2015 (oral), IwCLL 2015 (oral & poster), ASH 2016 (poster
Samples are available via application to the UK CLL Trials Biobank - https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fwww.liverpool.ac.uk%252Fclinical-research-and-training%252Fclinical-research%252Fgcp-laboratories%252Fuk-cll-biobank%252F%2FNBTI%2FFiDCAQ%2FAQ%2F78bdbdb0-494f-4788-9d86-cc0622e1af3d%2F1%2FaHRjURY9TQ&data=05%7C02%7Cleedseast.rec%40hra.nhs.uk%7C07b6e90ca509459a6eba08de3e560065%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C639016736251293184%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=7d9BrrGEFP698fIOgg9Dfc5LwT4zAMZcARXiUo9Qu6I%3D&reserved=0
REC name
Yorkshire & The Humber - Leeds East Research Ethics Committee
REC reference
09/H1306/54
Date of REC Opinion
25 Jun 2009
REC opinion
Further Information Favourable Opinion