Clinical trial NCT01678430: A Trial Looking at Ofatumumab for People With Chronic Lymphocytic Leukaemia Who Cannot Have More Intensive Treatment
Official title: A Randomised Investigation of Alternative Ofatumumab-containing Regimens in Less Fit Patients With CLL
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukaemia
Keywords: Chronic Lymphocytic Leukaemia
Less fit
CD20 antibody
Ofatumumab
Chlorambucil
Bendamustine
Lead sponsor: University of Liverpool
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
name: Napp Pharmaceuticals Limited
name: Chugai Pharma USA
First posted: 2012-09-05
Enrollment: 670
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare ofatumumab \& chlorambucil (O-Chl) versus ofatumumab \& bendamustine (O-B) in patients with Chronic Lymphocytic Leukaemia who are considered not fit enough for rituximab, fludarabine \& cyclophosphamide (R-FC).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

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

   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 splenomegaly.
   3. Massive (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
   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 od
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 excipients
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.

Primary outcomes:
measure: Progression-free survival
timeFrame: 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)
Secondary outcomes:
measure: Duration of response
timeFrame: 6 years (after 2 years follow up of the last patient recruited)
measure: Overall survival
timeFrame: 6 years (after 2 year follow up of the last patient recruited)
measure: Time to treatment failure
timeFrame: 6 years (after 2 year follow up of the last patient recruited)
measure: Toxicity
timeFrame: 6 years (after 2 years follow up of the last patient recruited)
measure: Treatment dose administered
timeFrame: 5 years (assuming last patient in receives 12 cycles of treatment)
measure: Quality of life
timeFrame: 6 years (after 2 years follow up of the last patient recruited)
measure: Health Economic analysis
timeFrame: 6 years (after 2 years follow up of the last patient recruited)
measure: Analysis of frailty and co-morbidity
timeFrame: Baseline, 2 months post treatment
measure: Predictive value of biomarkers
timeFrame: Baseline, every 6 months until 42 months from study entry, disease progression
measure: Response
timeFrame: Baseline; 2 months post treatment; 6 months post treatment
Other outcomes:
Locations:
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
state: Cheshire
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: Devon
city: Torquay
country: United Kingdom
facility: Torbay Hospital
state: Devon
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
state: Dorset
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital
state: Dorset
city: Colchester
country: United Kingdom
facility: Colchester General Hospital
state: Essex
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire Hospital
state: Hampshire
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: Hampshire
city: Enfield
country: United Kingdom
facility: Barnet and Chase Farm Hospitals
state: Hertfordshire
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
state: Kent
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital
state: Kent
city: Orpington
country: United Kingdom
facility: Princess Royal Hospital
state: Kent
city: Woolwich
country: United Kingdom
facility: Queen Elizabeth Hospital
state: London
city: Isleworth
country: United Kingdom
facility: West Middlesex University Hospital
state: Middlesex
city: Southall
country: United Kingdom
facility: Ealing Hospital
state: Middlesex
city: Uxbridge
country: United Kingdom
facility: Hillingdon Hospital
state: Middlesex
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
state: Northern Ireland
city: Bath
country: United Kingdom
facility: Royal United Hospital
state: Somerset
city: Weston-super-Mare
country: United Kingdom
facility: Weston General Hospital
state: Somerset
city: Burton-upon-Trent
country: United Kingdom
facility: Queens Hospital
state: Staffordshire
city: Gateshead
country: United Kingdom
facility: Queen Elizabeth Hospital
state: Tyne and Wear
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
state: West Midlands
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
state: West Yorkshire
city: Keighley
country: United Kingdom
facility: Airdale General Hospital
state: West Yorkshire
city: Leeds
country: United Kingdom
facility: St James University Hospital
state: West Yorkshire
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital
state: Wiltshire
city: Upton
country: United Kingdom
facility: Arrowe Park Hospital
state: Wirral
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Hospital
Study officials:
References: