A Randomised Investigation of Alternative Ofatumumab-containing Regimens in Less Fit Patients With CLL
试验速览
- 阶段
- 3 期
- 入组人数
- 670
- 试验地点
- 26
- 主要终点
- Progression-free survival
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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
干预措施: Ofatumumab (Drug)
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
干预措施: Chlorambucil (Drug)
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
干预措施: Ofatumumab (Drug)
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
干预措施: Bendamustine (Drug)
结局指标
主要结局
Progression-free survival
时间窗: 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.
次要结局
- Duration of response(6 years (after 2 years follow up of the last patient recruited))
- Overall survival(6 years (after 2 year follow up of the last patient recruited))
- Time to treatment failure(6 years (after 2 year follow up of the last patient recruited))
- Toxicity(6 years (after 2 years follow up of the last patient recruited))
- Treatment dose administered(5 years (assuming last patient in receives 12 cycles of treatment))
- Quality of life(6 years (after 2 years follow up of the last patient recruited))
- Health Economic analysis(6 years (after 2 years follow up of the last patient recruited))
- Analysis of frailty and co-morbidity(Baseline, 2 months post treatment)
- Predictive value of biomarkers(Baseline, every 6 months until 42 months from study entry, disease progression)
- Response(Baseline; 2 months post treatment; 6 months post treatment)