A Phase III, Open Label, Randomized, Multicenter Trial of Ofatumumab Maintenance Treatment Versus no Further Treatment in Subjects With Relapsed Chronic Lymphocytic Leukemia (CLL) Who Have Responded to Induction Therapy
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 480
- 试验地点
- 204
- 主要终点
- Progression-free Survival, as Assessed by the Investigator
研究概览
简要总结
The purpose of this study was to determine if maintenance therapy with ofatumumab would prolong remission in patients with CLL who have responded to second or third line treatment. This study would 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 would be conducted as a collaborative effort with GSK.
详细描述
The study met its primary objective at the protocol defined interim analysis (data cut-off 19-Jun-2014). The protocol-defined final analysis of the primary endpoint was performed when 280 PFS events were reached (data cut-off 20-Feb-2017).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults with documented diagnosis of CLL based on the modified IWCLL updated NCI-WG guidelines (Hallek, 2008)
- •At least PR according to the revised 2008 NCI-WG CLL criteria, within 3 months of the response assessment after the last dose of 2nd/3rd line treatment
- •The anti-leukemic treatment before study entry should have been at least 3 months or 3 cycles
- •ECOG Performance Status of 0-2
- •Signed written informed consent prior to performing any study-specific procedures
排除标准
- •Known primary or secondary fludarabine-refractory subjects, defined as treatment failure (failure to achieve a CR or PR) or disease progression within 6 months
- •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
- •Other anti-leukemic use of medications including glucocorticoids
- •Known HIV positive
- •Screening laboratory values: platelets <50 x 10x9/L, neutrophils<1.0 x 10x9/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
- •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).
研究组 & 干预措施
ARM B: Observation and assessments as per Arm A
Disease status assessments to determine subject response or progression performed approximately every 8 weeks for up to 2 years for both arms according to IWCLL criteria
干预措施: Observation (Other)
ARM A: Ofatumumab
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)
干预措施: Ofatumumab (Biological)
结局指标
主要结局
Progression-free Survival, as Assessed by the Investigator
时间窗: From randomization until progression or death (up to 79 months)
Progression-free survival is defined as the time from randomization to the date of disease progression (PD) or death due to any cause. PD was determined by the investigator according to the definitions of response in the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-Sponsored Working Group (NCI-WG) guidelines. According to the guidelines, PD is characterized by at least one of the following: lymphadenopathy (appearance of any new lesion such as enlarged lymph nodes (\>1.5 centimeter \[cm\]), spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site); an increase by 50% or more in the previously noted enlargement of the liver or spleen; an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter; transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukemia.
Progression-free Survival, as Assessed by the Independent Review Committee (IRC)
时间窗: From randomization until progression or death (up to 79 months)
Progression-free survival is defined as the time from randomization to the date of disease progression (PD) or death due to any cause. PD was determined by the IRC according to the definitions of response in the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-Sponsored Working Group (NCI-WG) guidelines. According to the guidelines, PD is characterized by at least one of the following: lymphadenopathy (appearance of any new lesion such as enlarged lymph nodes (\>1.5 centimeter \[cm\]), spleen or liver or other infiltrates or an increase by 50% or more in the greatest diameter of any previous site); an increase by 50% or more in the previously noted enlargement of the liver or spleen; an increase by 50% or more in the numbers of blood lymphocytes with at least 5000 lymphocytes per microliter; transformation to a more aggressive histology, or occurrence of cytopenia attributable to chronic lymphocytic leukemia.
次要结局
- Number of Participants Who Were Positive and Negative for Minimal Residual Disease (MRD) at Any Visit(From randomization until the end of the study (up to 88 months))
- Time to Next Therapy(From randomization until the end of the study (up to 88 months))
- Time to Progression After Next-line Therapy(From randomization until progression or death (up to 88 months))
- Number of Participants With an Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status at the Indicated Time Points(From randomization until the end of the study (up to 88 months))
- Number of Participants Who Received at Least One Transfusion During the Study(From randomization until the end of the study (up to 88 months))
- Change From Baseline (BL) in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Chronic Lymphocytic Leukaemia 16 Item Module (EORTC QLQ-CLL 16)(From randomization until the end of the study (up to 47 months))
- Overall Survival(From randomization until death (up to 88 months))
- Number of Participants With Improvement in Response From Baseline(From Baseline until the end of the study (up to 88 months))
- Progression-free Survival After Next-line Therapy(From randomization until progression or death (up to 88 months))
- Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)(From first dose of study medication until 60 days after the last dose of study medication or until the last observation at Visit 14 for AEs (up to 26 months) and until end of study for SAEs (88 months))
- Number of Participants With a Positive Anti-ofatumumab Antibody (Human Anti-human Antibody; HAHA) Result(Pre-dose (Visit 1), Months 7, 13, 19, and 25 during treatment and at 3 and 6 months after last ofatumumab dose (up to 30 months))
- Change From Baseline in the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score(From randomization until the end of the study (up to 47 months))
- Change From Baseline in the Quality of Life Status as Assessed by the EuroQol-5D (EQ-5D) Scale(From screening until the end of the study (up to 47 months))
- Number of Participants Diagnosed With Autoimmune Hemolytic Anemia (AIHA)(From randomization until the end of the study (up to 88 months))
- Mean Change From Baseline in the Immunoglobulin (Ig) Antibodies IgA, IgG, and IgM at Indicated Time Points(Baseline, every six months during treatment, and after last treatment visit and/or upon relapse (up to 88 months))
- Change From Baseline in Cluster of Differentiation (CD) CD5+CD19+ and CD5-CD19+ Cell Counts at the Indicated Time Points(Baseline and every two months from Month 3 until Month 25 and at every followup (up to 88 months))
- Cmax and Ctrough of Ofatumumab(Day 1 of Month 1 (Cycle 1 Week 1); Day 8 of Month 1 (Cycle 1 Week 2); and Month 7 (Cycle 4))
- Plasma Half-life (t1/2) of Ofatumumab(Day 1 of Month 1 (Cycle 1 Week 1); Day 8 of Month 1 (Cycle 1 Week 2); and Month 7 (Cycle 4))
- Number of Participants With the Indicated Constitutional or B-symptoms at the Indicated Time Points(From Screening until the end of the study (up to 88 months))
- Number of Participants With Grade 3 and Above Adverse Event of Infection(From first dose of study medication until 60 days after the last dose of study medication or until the last observation at Visit 14 (up to 26 months))
- Number of Participants With a Grade 3 or Grade 4 Myelosuppression (Anemia, Neutropenia, or Thrombocytopenia) at Indicated Time Points(From first dose of study medication until 60 days after the last dose of study medication or until the last observation at Visit 14 for AEs (up to 26 months) and until the end of the study for SAEs (88 months))
- Summary of Covariates to Compute Cox Proportional Hazards Regression Model for Relationship Between Investigator Assessed Progression-free Survival and the Indicated Prognostic Markers(From Baseline until the end of the study (up to 79 months))
- Total Plasma Clearance (CL) of Ofatumumab(Day 1 of Month 1 (Cycle 1 Week 1); Day 8 of Month 1 (Cycle 1 Week 2); and Month 7 (Cycle 4))
- AUC(0-tau) of Ofatumumab(Day 1 of Month 1 (Cycle 1 Week 1); Day 8 of Month 1 (Cycle 1 Week 2); and Month 7 (Cycle 4))
- Vss of Ofatumumab(Day 1 Month 1 ( Cycle 1) through Month 7 ( Cycle 4))