Combination fludarabine and cyclophosphamide (FC) plus Ofatumumab at Standard or Mega dose In Chronic lymphoid leukemia (CLL)

ISRCTN	ISRCTN51382468
DOI	https://doi.org/10.1186/ISRCTN51382468
Clinical Trials Information System (CTIS)	2011-000796-14
Protocol serial number	HM10/9652
Sponsor	Leeds Teaching Hospitals NHS Trust (UK)
Funder	GlaxoSmithKline

Submission date: 29/07/2011
Registration date: 21/09/2011
Last edited: 15/12/2021

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 of protocol

http://www.cancerresearchuk.org/cancer-help/trials/a-trial-comparing-different-doses-ofatumumab-chronic-lymphocytic-leukaemia-cosmic

Contact information

Prof Peter Hillmen
Scientific

Department of Haematology
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

Primary study design	Interventional
Study design	Phase II multi-centre randomised open parallel group trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Combination fludarabine and cyclophosphamide (FC) plus Ofatumumab at Standard or Mega dose In Chronic lymphoid leukemia (CLL): a phase II, multi-centre, randomised, open, parallel group trial
Study acronym	COSMIC
Study objectives	This trial will assess the efficacy of standard dose and high (mega) dose of ofatumumab in combination with chemotherapy (fludarabine and cyclophosphamide) in relapsed B-CLL patients.
Ethics approval(s)	Research Ethics Committee: Yorkshire & The Humber – Leeds East, 24/10/2011, ref: 11/YH/0260
Health condition(s) or problem(s) studied	Chronic Lymphocytic Leukaemia (CLL)
Intervention	1. Fludarabine, cyclophosphamide and standard dose ffatumumab (Standard Of-FC): 1.1. Fludarabine (oral) - 24mg/m2/day - Day 1 to 5 (Cycle 1 to 6) 1.2. Cyclophosphamide (oral) - 150mg/m2/day - Day 1 to 5 (Cycle 1 to 6) 1.3. Ofatumumab [intravenous (IV)] - 300mg - Day 1 and 1000mg Day 8 (Cycle 1 only) 1.4. Ofatumumab (IV) - 1000mg - Day 1 (Cycle 2 to 6) 2. Fludarabine, cyclophosphamide and high dose ofatumumab (Mega-Of-FC): 2.1. Fludarabine (oral) - 24mg/m2/day - Day 1 to 5 (Cycle 1 to 6) 2.2. Cyclophosphamide (oral) - 150mg/m2/day - Day 1 to 5 (Cycle 1 to 6) 2.3. Ofatumumab (IV) - 300mg - Day 1 (Cycle 1) followed by 2000mg weekly for 8 doses, followed by 2000mg monthly for 3 doses
Intervention type	Drug
Phase	Phase II
Drug / device / biological / vaccine name(s)	Fludarabine, cyclophosphamide, ofatumumab
Primary outcome measure(s)	Proportion of patients achieving a Complete Response (CR or CR(i)), as defined by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria. Measured 3 months after the therapy.
Key secondary outcome measure(s)	1. Proportion of patients with undetectable minimal residual disease (MRD) 2. Overall response rate defined as complete or partial remission by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria 3. Progression-free survival at 2 years 4. Overall survival at 2 years 5. Time to MRD relapse in MRD negative patients 6. Safety and toxicity
Completion date	01/07/2013

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	82
Total final enrolment	62
Key inclusion criteria	1. At least 18 years old 2. Chronic lymphocytic leukaemia requiring therapy 3. Previous treatment with at least one chemotherapeutic regime 4. Be capable of giving written informed consent 5. World Health Organisation (WHO) performance status (PS) of 0, 1, or 2 6. Life expectancy of at least 12 weeks 7. Considered fit enough to receive fludarabine-based combinations
Key exclusion criteria	1. Fludarabine refractory: defined as no response to or relapse within 6 months of fludarabine alone or in combination with cyclophosphamide (FC) 2. Relapse within 12 months of FC with rituximab (FCR) 3. Deletion of chromosome 17p on fluorescent in-situ hybridisation (FISH) [will be performed in Haematological Malignancy Diagnostic Service (HMDS) at screening] 4. Previous treatment with ofatumumab either alone or in combination with chemotherapy 5. Toxicity attributable to purine analogues such as autoimmune haemolytic anaemia, neurological toxicity or allergy 6. Active infection 7. Other severe, concurrent (particularly cardiac or pulmonary) diseases or mental disorders that could interfere with their ability to participate in the study 8. Patients with a creatinine clearance of less than 30ml/min (either measured or derived by the Cockcroft-Gault formula) 9. Pregnant, lactating or women of child bearing potential unwilling to use medically approved contraception whilst receiving treatment and for 12 months after treatment has finished 10. 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 has finished, unless they are surgically sterile 11. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per Investigator assessment) 12. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrolment, whichever is longer, or currently participating in any other interventional clinical study 13. Other past or current malignancy. Subjects who have been free of malignancy for at least 2 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible. 14. Prior treatment with anti-CD20 monoclonal antibody or alemtuzumab within 3 months prior to start of therapy 15. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C 16. History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae 17. Known human immunodeficiency (HIV) positive 18. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomisation, congestive heart failure New York Heart Association (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities. 19. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the Investigator may represent a risk for the patient. 20. 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 21. 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 screening laboratory values: 21.1. Platelets <50 x 109/L (unless due to involvement by CLL) 21.2. Neutrophils <1.0 x 109/L (unless due to involvement by CLL) 21.3. Creatinine clearance below 30ml/min (between 30 and 60ml/min the fludarabine dose will be reduced) 21.4. Total bilirubin >1.5 times upper normal limit (unless due to CLL involvement of liver or a known history of Gilberts disease) 21.5. Alanine aminotransferase (ALT) >2.5 times upper normal limit (unless due to CLL involvement of liver) 21.6. Alkaline phosphatase >2.5 times upper normal limit (unless due to disease involvement of the liver or bone marrow by CLL)
Date of first enrolment	01/01/2012
Date of final enrolment	01/07/2013

Locations

Countries of recruitment

United Kingdom
England

Study participating centre

St James's University Hospital

Leeds
LS9 7TF
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary
IPD sharing plan	Not provided at time of registration

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		01/08/2021	04/06/2021	Yes	No
Protocol article	protocol	20/09/2016		Yes	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

04/06/2021: The following changes have been made:
1. Publication reference added.
2. The total final enrolment number has been added from the reference.
26/06/2017: Publication and dissemination plan added.
21/09/2016: Publication reference added.