RIAltO: A Trial Looking at Ofatumumab for People With Chronic Lymphocytic Leukaemia Who Cannot Have More Intensive Treatment

Sponsor

University of Liverpool (Other)

Overall Status

Unknown status

CT.gov ID

NCT01678430

Collaborator

GlaxoSmithKline (Industry), Napp Pharmaceuticals Limited (Industry), Chugai Pharma USA (Industry)

670

Enrollment

Locations

Arms

Duration (Months)

23.9

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukaemia	Drug: Ofatumumab Drug: Chlorambucil Drug: Bendamustine	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

670 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Dec 1, 2011

Anticipated Primary Completion Date :

Dec 1, 2017

Anticipated Study Completion Date :

Dec 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ofatumumab-Chlorambucil Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8; cycle 2 onwards: 1000mg iv day 1 Chlorambucil: 10mg/m2 po days 1-7	Drug: Ofatumumab Other Names: Arzerra Drug: Chlorambucil Other Names: Leukeran
Experimental: Ofatumumab-Bendamustine Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8; cycle 2 onwards: 1000mg iv day 1 Bendamustine: 70mg/m2 iv days 1 and 2	Drug: Ofatumumab Other Names: Arzerra Drug: Bendamustine Other Names: Levact

Arm

Intervention/Treatment

Active Comparator: Ofatumumab-Chlorambucil

Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8; cycle 2 onwards: 1000mg iv day 1 Chlorambucil: 10mg/m2 po days 1-7

Drug: Ofatumumab

Other Names:

Arzerra

Drug: Chlorambucil

Other Names:

Leukeran

Experimental: Ofatumumab-Bendamustine

Ofatumumab cycle 1: 300mg iv day 1, 1000mg iv day 8; cycle 2 onwards: 1000mg iv day 1 Bendamustine: 70mg/m2 iv days 1 and 2

Drug: Ofatumumab

Other Names:

Arzerra

Drug: Bendamustine

Other Names:

Levact

Outcome Measures

Primary Outcome Measures

Progression-free survival [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)]
Calculated from the date of randomisation to the date of progression or death, or the censor date.

Secondary Outcome Measures

Duration of response [6 years (after 2 years follow up of the last patient recruited)]
Response duration is defined as the time from when the criteria for partial or complete response are met until the first documentation of relapse or progression.
Overall survival [6 years (after 2 year follow up of the last patient recruited)]
Overall survival is defined as the time from initiation of study treatment to death, irrespective of cause or subsequent treatment. Patients still alive at the time of analysis will be censored at the date last seen alive at last follow up.
Time to treatment failure [6 years (after 2 year follow up of the last patient recruited)]
Time to treatment failure is defined as the time from initiation of study treatment to death, disease progression, or initiation of alternative treatment due to failure to achieve a complete or partial response to the study treatment.
Toxicity [6 years (after 2 years follow up of the last patient recruited)]
Haematological toxicity will be reported in accordance with the 2008 NCI/IWCLL guidelines. Non-haematological toxicity will be reported in accordance with the current Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Treatment dose administered [5 years (assuming last patient in receives 12 cycles of treatment)]
The number of cycles of treatment and cumulative dose of individual drugs administered will be summarised for each treatment group separately and compared across treatment groups
Quality of life [6 years (after 2 years follow up of the last patient recruited)]
Quality of life will be assessed using the EQ-5D; EQ-VAS; EORTC QLQ-C30 and EORTC QLQ-CLL16 questionnaires. To standardise the raw scores, they will be linearly transformed into 0-to-100 scores.
Health Economic analysis [6 years (after 2 years follow up of the last patient recruited)]
The economic evaluation will take the form of a cost-effectiveness analysis with the differential cost of the alternative treatments will be related to their differential benefits in terms of quality-adjusted life years (QALYs). Incremental cost-utility ratios will be estimated based on QALY estimates. A range of uni- and multi-variate, as well as probabilistic sensitivity analyses will be conducted to assess the robustness of the analysis. The use of bootstrapping and cost-effectiveness acceptability curves will facilitate a measure of variability around cost-effectiveness estimates. Sensitivity analysis will be used to consider the importance of sources of uncertainty other than sample variation (e.g. unit costs, discount rates). A model-based extrapolation of the trial results will be performed to explore the impact of a longer analytic time horizon, and consideration of health outcomes on the treatment cost-effectiveness.
Analysis of frailty and co-morbidity [Baseline, 2 months post treatment]
Patients outcomes will be compared across patient subgroups defined by CIRS, performance status, Vulnerable Elders Survey-13, Groningen Frailty Index (GFI) questionnaires and the Timed 'Up and Go' test.
Predictive value of biomarkers [Baseline, every 6 months until 42 months from study entry, disease progression]
Patient outcomes will be compared across patient subgroups defined by clinical (e.g. age, sex, stage) and laboratory (e.g. chromosomal, abnormalities, IGHV mutation status, TP53 mutation status).
Response [Baseline; 2 months post treatment; 6 months post treatment]
Response following initial therapy will be assessed in accordance with the revised (2008) NCI/IWCLL response criteria applicable to CLL. Minimal residual disease will be assessed by multicolour flow cytometric analysis of bone marrow aspirate samples taken 2 months after completing treatment and of blood samples taken 2 and 6 months after completing treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

CLL/SLL requiring treatment by NCI/IWCLL 2008 criteria. At least one of the following criteria:
Progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia.
Massive (i.e. 6 cm below the left costal margin) or progressive or symptomatic splenomegaly.
Massive (i.e. 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of less than 6 months.
No prior cytotoxic or targeted therapy for CLL
Full-dose R-FC considered inappropriate for at least one of the following reasons
Age 75 or greater
WHO performance status 2 or 3
Cardiac impairment (NYHA class II)
Respiratory impairment (bronchiectasis or moderate COPD)
Renal impairment (estimated Glomerular Filtration Rate (eGFR) 10-30 ml/min)
Any other significant co-morbidity or factor that makes R-FC inappropriate
Considered able to tolerate Chl at the dose used in the LRF CLL4 trial (10mg/m2 d1-7)
Written informed consent

Exclusion Criteria:

Neutrophil count less than 1.0 x 109/l or platelet count less than 50 x 109/l unless due to CLL
Uncontrolled auto-immune haemolytic anaemia or thrombocytopenia
Active infection
Seropositivity for HIV, HCV or HBV (surface antigen or and core antibody)
Severe renal impairment (eGFR less than 10ml/min)
Severe hepatic impairment (serum bilirubin more than twice the upper limit of normal) unless due to CLL or Gilbert's syndrome.
Concurrent treatment with glucocorticoids equivalent to more than prednisolone 20mg od
Prior treatment with monoclonal antibody therapy within the last 3 months.
Yellow fever vaccination within 4 weeks prior to treatment start
Known hypersensitivity to ofatumumab, bendamustine or chlorambucil or any of their excipients
CNS involvement with CLL
History of Richter transformation
Concomitant malignancies within the last 3 years except successfully treated non-melanoma skin cancer or carcinoma in situ.
Major surgery within 28 days prior to randomisation
WHO performance status 4
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.
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
Treatment within a clinical trial within 30 days prior to trial entry.
Adult patient under tutelage (not competent to sign informed consent).
Pregnant or lactating women.
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.
Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.

Contacts and Locations

Locations

	Site	City	State	Country
1	Countess of Chester Hospital	Chester	Cheshire	United Kingdom
2	Derriford Hospital	Plymouth	Devon	United Kingdom
3	Torbay Hospital	Torquay	Devon	United Kingdom
4	Royal Bournemouth Hospital	Bournemouth	Dorset	United Kingdom
5	Dorset County Hospital	Dorchester	Dorset	United Kingdom
6	Colchester General Hospital	Colchester	Essex	United Kingdom
7	Basingstoke and North Hampshire Hospital	Basingstoke	Hampshire	United Kingdom
8	Southampton General Hospital	Southampton	Hampshire	United Kingdom
9	Barnet and Chase Farm Hospitals	Enfield	Hertfordshire	United Kingdom
10	Kent and Canterbury Hospital	Canterbury	Kent	United Kingdom
11	Maidstone Hospital	Maidstone	Kent	United Kingdom
12	Princess Royal Hospital	Orpington	Kent	United Kingdom
13	Queen Elizabeth Hospital	Woolwich	London	United Kingdom
14	West Middlesex University Hospital	Isleworth	Middlesex	United Kingdom
15	Ealing Hospital	Southall	Middlesex	United Kingdom
16	Hillingdon Hospital	Uxbridge	Middlesex	United Kingdom
17	Belfast City Hospital	Belfast	Northern Ireland	United Kingdom
18	Royal United Hospital	Bath	Somerset	United Kingdom
19	Weston General Hospital	Weston-super-Mare	Somerset	United Kingdom
20	Queens Hospital	Burton-upon-Trent	Staffordshire	United Kingdom
21	Queen Elizabeth Hospital	Gateshead	Tyne and Wear	United Kingdom
22	Queen Elizabeth Hospital	Birmingham	West Midlands	United Kingdom
23	Bradford Royal Infirmary	Bradford	West Yorkshire	United Kingdom
24	Airdale General Hospital	Keighley	West Yorkshire	United Kingdom
25	St James University Hospital	Leeds	West Yorkshire	United Kingdom
26	Salisbury District Hospital	Salisbury	Wiltshire	United Kingdom
27	Arrowe Park Hospital	Upton	Wirral	United Kingdom
28	Royal Liverpool Hospital	Liverpool		United Kingdom