COSMIC Version 1.0
Research type
Research Study
Full title
Combination FC plus Ofatumumab at Standard or Mega dose In CLL
IRAS ID
76052
Contact name
Peter Hillmen
Sponsor organisation
The Leeds Teaching Hospitals NHS Trust
Eudract number
2011-000796-14
ISRCTN Number
n/a
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 lymph 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. Although the treatment of CLL has improved over recent years, the treatment of relapsed and refractory (not responsive to standard treatment) CLL remains difficult. The choice of treatment for relapsed CLL depends on various factors such as previous treatment, length of remission, age and performance status of the patient, stage of the disease and the biological characters of the malignant cellfluarabine and Cyclophosphamide (FC) are two chemotherapy drugs that together have proved to be effective at treating CLL. Ofatumumab is an antibody which targets CLL and works in a different way from chemotherapy. It is found to be effective on its own to a certain extent in treating refractory CLL. However, it is thought that adding Ofatumumab to chemotherapy (such as F and C) may improve response rates, although the best dose to be given is not known.This trial will recruit previously treated CLL patients who now require further treatment. It will assess the responses of patients who are treated with F and C combined with a standard dose of ofatumumab and the responses of those treated with F and C combined with a high dose of ofatumumab.
Summary of results:
About this trial
People with chronic lymphocytic leukaemia (CLL) were usually treated with chemotherapy plus an antibody drug that helps the immune system attack cancer cells. One of these drugs is ofatumumab. It can be given in very high doses when used on its own, or in lower doses when combined with chemotherapy—and both approaches produce good responses. Because most tumour shrinkage happens early during treatment, researchers wondered whether giving a higher, more intensive dose of ofatumumab early on could improve results.
The COSMIC study was a phase II clinical trial for people whose CLL had come back after previous treatment. Everyone received standard chemotherapy (either fludarabine–cyclophosphamide or bendamustine). Patients were randomly placed into one of two groups:
• Standard-dose ofatumumab (sOf)
• High-dose, more intensive ofatumumab (megaOf)
Both groups had six 28-day treatment cycles. The high-dose group received larger and more frequent doses of ofatumumab, especially in the first two cycles.
The main aim was to see how many patients achieved a complete remission (CR) or near-complete remission (CRi) to decide whether either dose combination was effective enough to justify larger studies. Researchers also looked at how many cancer cells remained after treatment (minimal residual disease or MRD), overall response rates, how long people stayed well before the disease worsened, survival, and side effects.Results
Between 2012 and 2016, 62 patients in the UK joined the study (fewer than originally planned). Most were men, about half were under 65, and about half were in good general health. Most had received only one previous treatment, usually fludarabine, and many had stayed in remission for more than two years after their last treatment. Many also had features linked with higher-risk disease. No one had a 17p chromosome deletion (a high-risk abnormality), because this would have excluded them from taking part in a trial involving chemotherapy.
About two-thirds of participants completed all six treatment cycles. The main goal—complete remission—was reached at similar rates in both groups:
• Standard-dose: 7 out of 32 patients (22%)
• High-dose: 7 out of 29 patients (24%)
These numbers were too low to justify moving to a larger trial. People who had been treated with fludarabine before were less likely to respond than those who had not.
Giving higher, more intensive doses of ofatumumab did not improve remission rates when combined with chemotherapy for relapsed CLL. Both schedules were generally well tolerated, and overall results were similar to other chemotherapy-based treatments.
Today, many people with CLL receive newer, targeted treatments instead of chemotherapy. However, chemotherapy may still be an option for a small number of lower-risk patients who prefer treatment that lasts only a set period of time. Although high-dose ofatumumab did not help in this setting, researchers suggest it may still be worth testing in combination with modern targeted drugs.Conclusion
Increasing the dose of ofatumumab early in treatment did not improve outcomes, so this approach is not recommended.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%2F-R-CAQ%2FAQ%2F1192334c-f851-46d5-890f-b87562a7992b%2F1%2FcCjlB7MHU-&data=05%7C02%7Cleedseast.rec%40hra.nhs.uk%7C8b3257e7c5184bf9967908de3e529021%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C639016721503974429%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=tzZzYcGLQoXZcNHeoQRu%2F%2BFm4Y1k%2FZVHPzAmdb3cP8E%3D&reserved=0
REC name
Yorkshire & The Humber - Leeds East Research Ethics Committee
REC reference
11/YH/0260
Date of REC Opinion
24 Oct 2011
REC opinion
Further Information Favourable Opinion