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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Chronic Lymphocytic Leukaemia

Intervention / Treatment
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* Drug: Ofatumumab
* Drug: Chlorambucil
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ofatumumab-Chlorambucil<br>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<br> <br> * Other names: Arzerra;Drug: Chlorambucil<br> <br> * Other names: Leukeran;|
| Experimental: Ofatumumab-Bendamustine<br>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<br> <br> * Other names: Arzerra;Drug: Bendamustine<br> <br> * Other names: Levact;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Calculated from the date of randomisation to the date of progression or death, or the censor date. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response | 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. | 6 years (after 2 years follow up of the last patient recruited) | 
| Overall survival | 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. | 6 years (after 2 year follow up of the last patient recruited) | 
| Time to treatment failure | 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. | 6 years (after 2 year follow up of the last patient recruited) | 
| Toxicity | 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. | 6 years (after 2 years follow up of the last patient recruited) | 
| Treatment dose administered | 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 | 5 years (assuming last patient in receives 12 cycles of treatment) | 
| Quality of life | 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. | 6 years (after 2 years follow up of the last patient recruited) | 
| Health Economic analysis | 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. | 6 years (after 2 years follow up of the last patient recruited) | 
| Analysis of frailty and co-morbidity | 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. | Baseline, 2 months post treatment | 
| Predictive value of biomarkers | 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). | Baseline, every 6 months until 42 months from study entry, disease progression | 
| Response | 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. | Baseline; 2 months post treatment; 6 months post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ofatumumab, Chronic Lymphocytic Leukaemia, Less fit, CD20 antibody, Chlorambucil, Bendamustine