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A Randomised Investigation of Alternative Ofatumumab-containing Regimens in Less Fit Patients With CLL

Phase 3
18 Years
Open (Enrolling)
Chronic Lymphocytic Leukaemia

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Trial Information

A Randomised Investigation of Alternative Ofatumumab-containing Regimens in Less Fit Patients With CLL

Chlorambucil (Chl) has been the mainstay of CLL treatment for half a century. However,
frontline treatment has improved considerably over the last decade, first by the advent of
fludarabine plus cyclophosphamide (FC), and more recently by the addition of the anti-CD20
antibody, rituximab, to FC. Although FC-based regimens are considerably more effective than
Chl, they are also associated with greater toxicity which makes them inappropriate for less
fit patients. This is an important consideration, given that CLL predominantly affects older
people who tend to have more co-morbidity. Although a single-arm phase II study (Roche
MO20927; NCRI CLL208) has shown that R-Chl is safe and effective, there are no phase III
data proving the benefit of adding an anti-CD20 antibody to Chl. This question is currently
being addressed by a phase III RCT of Chl with or without ofatumumab (GSK OMB110911 /
COMPLEMENT-1 / NCRI CLL7). Ofatumumab is a fully human anti-CD20 antibody that binds to an
epitope distinct from that of rituximab and produces more complement-dependent cytotoxicity.
The RIAltO trial is a direct follow-on to the NCRI CLL7 phase III RCT trial in less fit
patients and therefore the Ofatumumab dose has been selected to mirror the regimen used in
that trial.

Inclusion Criteria:

1. CLL/SLL requiring treatment by NCI/IWCLL 2008 criteria. At least one of the following

1. Progressive marrow failure as manifested by the development of, or worsening of,
anaemia and/or thrombocytopenia.

2. Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic

3. Massive (i.e. 10 cm in longest diameter) or progressive or symptomatic

4. Progressive lymphocytosis with an increase of more than 50% over a 2-month
period or lymphocyte doubling time (LDT) of less than 6 months.

2. No prior cytotoxic or targeted therapy for CLL

3. Full-dose R-FC considered inappropriate for at least one of the following reasons

1. Age 75 or greater

2. WHO performance status 2 or 3

3. Cardiac impairment (NYHA class II)

4. Respiratory impairment (bronchiectasis or moderate COPD)

5. Renal impairment (estimated Glomerular Filtration Rate (eGFR) 10-30 ml/min)

6. Any other significant co-morbidity or factor that makes R-FC inappropriate

4. Considered able to tolerate Chl at the dose used in the LRF CLL4 trial (10mg/m2 d1-7)

5. Written informed consent

Exclusion Criteria:

1. Neutrophil count less than 1.0 x 109/l or platelet count less than 50 x 109/l unless
due to CLL

2. Uncontrolled auto-immune haemolytic anaemia or thrombocytopenia

3. Active infection

4. Seropositivity for HIV, HCV or HBV (surface antigen or and core antibody)

5. Severe renal impairment (eGFR less than 10ml/min)

6. Severe hepatic impairment (serum bilirubin more than twice the upper limit of normal)
unless due to CLL or Gilbert's syndrome.

7. Concurrent treatment with glucocorticoids equivalent to more than prednisolone 20mg

8. Prior treatment with monoclonal antibody therapy within the last 3 months.

9. Yellow fever vaccination within 4 weeks prior to treatment start

10. Known hypersensitivity to ofatumumab, bendamustine or chlorambucil or any of their

11. CNS involvement with CLL

12. History of Richter transformation

13. Concomitant malignancies within the last 3 years except successfully treated
non-melanoma skin cancer or carcinoma in situ.

14. Major surgery within 28 days prior to randomisation

15. WHO performance status 4

16. Severe cardiac disease including unstable angina, acute myocardial infarction within
six months prior to randomization, congestive heart failure (NYHA III-IV), and
arrhythmia (excluding extra systoles or minor conduction abnormalities) unless
controlled by therapy.

17. Any serious underlying medical or psychological conditions, which could impair the
ability of the patient to participate in the trial or compromise ability to give
informed consent

18. Treatment within a clinical trial within 30 days prior to trial entry.

19. Adult patient under tutelage (not competent to sign informed consent).

20. Pregnant or lactating women.

21. Women of childbearing potential, including women whose last menstrual period was less
than one year prior to screening, unable or unwilling to use adequate contraception
from study start to one year after the last dose of protocol therapy. Adequate
contraception is defined as hormonal birth control, intrauterine device, double
barrier method or total abstinence.

22. Male subjects unable or unwilling to use adequate contraception methods from study
start to one year after the last dose of protocol therapy.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Description:

Calculated from the date of randomisation to the date of progression or death, or the censor date.

Outcome Time Frame:

There are three pre-planned analyses of the PFS primary endpoint: end recruitment (approx 150 events); 300 events (after a minimum 12 months follow up for all patients), 400 events (after a minimum 24 months follow up for all patients)

Safety Issue:



United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

December 2011

Completion Date:

December 2017

Related Keywords:

  • Chronic Lymphocytic Leukaemia
  • Chronic Lymphocytic Leukaemia
  • Less fit
  • CD20 antibody
  • Ofatumumab
  • Chlorambucil
  • Bendamustine
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid