Ofatumumab Maintenance Treatment vs No Further Treatment in Relapsed CLL Responding to Induction Therapy (PROLONG)

• Overall survival [ Time Frame: [Time frame: 5 year f/u after end of study, ~2021] ] [ Designated as safety issue: No ]
• Clinical benefit, safety, tolerability [ Time Frame: [Time frame: 280 events, ~72 months] ] [ Designated as safety issue: Yes ]
• Pharmacokinetic- plasma ofatumumab concentrations (ARM A only) [ Time Frame: [Time frame: 280 events, ~72 months] ] [ Designated as safety issue: No ]

• Progression free survival after next-line therapy [ Time Frame: From time of randomization until progression or death following next-line therapy ] [ Designated as safety issue: No ]
• Evaluation of myelosuppression, frequency of transfusions, Immunoglobulin serum levels, incidence of infections and autoimmune hemolytic anemia, [ Time Frame: From time of randomization until 60 days after last treatment/observation visit ] [ Designated as safety issue: Yes ]
• Pharmacokinetic- plasma ofatumumab concentrations (ARM A only) [ Time Frame: From time of first infusion until 6 months after last dose ] [ Designated as safety issue: No ]
• Time to next CLL therapy [ Time Frame: From time of randomization until to date of of receiving the next CLL treatment ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: From time of randomization to date of death (5 year f/u after end of study) ] [ Designated as safety issue: No ]
• Improvement in response [ Time Frame: From time of randomization to end of study ] [ Designated as safety issue: No ]

The purpose of this study is to determine if maintenance therapy with ofatumumab will prolong remission in patients with CLL who have responded to second or third line treatment. This study will also evaluate the safety of ofatumumab maintenance compared to observation (the current standard of care). This study was co-developed with the HOVON and NORDIC CLL group and will be conducted as a collaborative effort with GSK.

• Biological: Ofatumumab
  Ofatumumab for maintenance therapy as IV infusions every 8 weeks . The first dose will be 300 mg followed 1 week later by 1000 mg and 1000 mg every 8 weeks thereafter for up to 2 years).
• Other: No Intervention
  Observation/Safety Evaluation

• Experimental: ARM A: Ofatumumab
  Ofatumumab Treatment: 300 mg IV Week 1 followed by 1000 mg IV Week 2 1000 mg IV (a dose every 8 weeks for up to 2 years following the first 1000 mg dose)
  Intervention: Biological: Ofatumumab
• No Intervention: ARM B: No Treatment
  No further treatment (observation and assessments as per ARM A)
  Intervention: Other: No Intervention

Inclusion Criteria:

• Adults with documented diagnosis of CLL based on the modified IWCLL updated NCI-WG guidelines (Hallek, 2008)
• CR or PR according to the revised 2008 NCI-WG CLL criteria, confirmed by CT scan, after second or third line treatment
• The anti-leukemic treatment before study entry should have been at least 4 months of monotherapy with alkylating agents and/or at least 4 consecutive cycles of polychemotherapy (e.g. CVP), fludarabine-containing chemotherapy or immunochemotherapy
• ECOG Performance Status of 0-2
• Signed written informed consent prior to performing any study-specific procedures

Exclusion Criteria:

• Primary or secondary fludarabine-refractory subjects, defined as treatment failure (failure to achieve a CR or PR) or disease progression within 6 months of last anti-leukemic therapy. Note: Subjects refractory to rituximab therapy as last therapy are permitted.
• Prior maintenance therapy
• Known transformation of CLL (eg.Richter's transformation), prolymphocytic leukemia (PLL), or CNS involvement of CLL
• Active Autoimmune hemolytic anemia (AIHA) requiring treatment except if in the opinion of the investigator and medical monitor it is thought not to affect the subject's safety, the conduct of the study or the interpretation of the data
• Previous autologous or allogeneic stem cell transplantation
• Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis B or C
• Other past or current malignancy (with the exception of basal cell carcinoma or the skin or in situ carcinoma of the cervix or breasts) unless the tumor was successfully treated with curative intent at least 2 years prior to trial entry except if in the opinion of the investigator and medical monitor it is thought not to affect the subject's safety, the conduct of the study or the interpretation of the data
• Clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months prior to screening, congestive heart failure, and arrhythmia requiring therapy, with the exception of exta systoles or minor conduction abnormalities except if in the opinion of the investigator and medical monitor it is thought not to affect the subject's safety, the conduct of the study or the interpretation of the data
• History of significant cerebrovascular disease or event with symptoms or sequelae
• Significant concurrent, uncontrolled medical condition that in the opinion of the investigator or GSK medical monitor contraindicates participation in this study
• Glucocorticoid unless given in doses <100 mg/day hydrocortisone (or equivalent dose of other glucocorticoid) if for exacerbation other than CLL (e.g. asthma)
• Known HIV positive
• Screening laboratory values: platelets <50 x 109/L, neutrophils<1.0 x 109/L, Creatinine > 1.5 X upper normal limit (unless normal creatinine clearance), total bilirubin >1.5 X upper normal limit, ALT >2.5 X upper normal limit (unless due to liver involvement of CLL), alkaline phosphase > 2.5 X upper normal limit
• Known or suspected hypersensitivity to ofatumumab that in the opinion of the investigator or medical monitor contraindicates study participation
• Subjects who have received treatment with any non-marketed drug substance or experimental therapy within 5-terminal half-lives or 4 weeks whichever is longer prior to first dose of study medication or currently participating in any other interventional clinical study Note: Participation in any other interventional clinical study after disease progression during post PD follow-up is permitted OR participation in any other interventional clinical study where the subject received ONLY standard approved CLL therapy is permitted
• Lactating women, women with a positive pregnancy test at Visit 1 or women (of childbearing potential) as well as men with partners of childbearing potential, who are not willing to use adequate contraception from study start through one year following last ofatumumab dose. Adequate contraception is defined as abstinence, oral hormonal birth control, implants of levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive patches, intrauterine device, and male partner sterilization if male partner is sole partner for that subject. For females in the USA, the use of a double barrier method is also considered adequate (condom or occlusive cap plus spermicidal agent).