A Phase II Open-label Study of Single Agent Ofatumumab in Patients With Relapsed and/or Refractory Diffuse Large B Cell Non Hodgkin Lymphomas
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 11
- 试验地点
- 3
- 主要终点
- Overall Response (OR)
研究概览
简要总结
This is a phase II open label study that looks at the efficacy and toxicity of Ofatumumab monotherapy in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL). Patients will receive weekly infusions of Ofatumumab of 1000 mg each for 8 weeks (induction phase) followed by continuing the study drugs every other week in subsequent cycles (maintenance phase). Each 4 weeks of therapy will be calculated as one cycle. Treatment will continue until disease progression, toxicity, patient's withdrawal, or investigator's discretion.
详细描述
Ofatumumab is a fully human monoclonal IgG1κ-antibody targeting a novel cluster of differentiation antigen 20(CD20)-epitope. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic leukemia cell-lines with low CD20-antigen density and an increased expression of complement inhibitory molecules. Ofatumumab was superior to rituximab in its ability to induce lysis in B-cell lines and also killed fresh B-chronic lymphocytic leukemia cells that were resistant to rituximab. Ofatumumab has a slower off-rate and more stable CD20 binding in comparison with rituximab and targets a different epitope of the CD20 antigen than rituximab [Teeling, 2004, Teeling, 2006]. In cynomolgus monkeys, the duration of B-cell depletion from peripheral blood and lymph nodes induced by ofatumumab was longer than that of rituximab [Dechant, 2003].
Ofatumumab's ability to induce complement-dependent cytotoxicity (CDC) has been specifically studied in isolated lymphoma cells from chemotherapy refractory DLBCL patients [Cillessen, 2007]. Ofatumumab and rituximab induced CDC of all DLBCL samples tested, including the DLBCL cell lines SUDHL-4, SUDHL-5 and HT and lymphoma cells derived from ten chemotherapy-refractory DLBCL patients.
Ofatumumab was significantly more effective in inducing CDC in nine of the ten DLBCL tumor samples when compared with rituximab (p=0.001). The lethal doses (LD50) for ofatumumab (0.1 ± 2.8 μg/mL) were significantly lower when compared with the LD50 for rituximab (6.4 ± 4.9μg/mL, p=0.04). Sensitivity of DLBCL patient cells to ofatumumab- and rituximab-induced CDC negatively correlated with expression of complement defense molecule CD59, but not with expression of CD46 or CD55. Functional inhibition of CD55 and CD59 using blocking mAb demonstrated that ofatumumab-induced CDC of DLBCL tumor cells was less sensitive to expression of these complement defense molecules than rituximab-induced CDC.
Thus, chemotherapy-refractory DLBCL cases are sensitive to CD20 mAb-induced CDC with ofatumumab being the most effective mAb, especially in patients expressing high levels of CD59.
Safety and efficacy of ofatumumab, has been analyzed in multicenter dose-escalating phase I/II studies in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). Three cohorts of patients including 33 patients with relapsed or refractory CLL received weekly infusions of ofatumumab for four weeks as follows: cohort A, the first infusion was 100 mg and three subsequent infusions of 500 mg; cohort B, the first infusion was 300 mg and three subsequent infusions of 1000 mg; cohort C, the first infusion was 500 mg and three subsequent infusions of 2000 mg. The maximum tolerated dose was not reached. The majority of related adverse events occurred at first infusion, and the number of adverse events decreased at each subsequent infusion. Seventeen (51%) of 33 patients experienced infections, 88% of them of grade 1-2. One event of interstitial pneumonia was fatal; all other cases resolved within one month. The response rate in cohort C was 50% (13/26 patients) [Coiffier, 2008].
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 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
- •Relapsed and/or refractory DLBCL,not HSCT candidates. Pts must have failed standard of care (SOC) therapy w/rituximab plus CHOP or its equivalent & not considered hematopoietic stem cell transplant (HSCT) candidates based on investigator's discretion
- •Pts must have measurable disease radiographically on CT and/or PET scans and/or bone marrow biopsy.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- •Age ≥18 years. No upper limit of age
- •Life expectancy of 6 months or more based on investigator's best estimate.
- •Pts able to read, understand, & sign informed consent
- •Evidence of CD20 positivity in treated pts, using flow or immunohistochemistry.
- •Pts will be stratified based on bulk of disease (bulk defined as any area w/ more than 5cm in greatest dimension)
- •Pts must agree to an acceptable form of birth control
排除标准
- •Other histologies of non-Hodgkin's lymphoma (NHL)
- •Known central nervous system (CNS) involvement with NHL
- •Known HIV positive status
- •Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment.
- •Corticosteroid use is allowed as long as it is for non-lymphoma related causes such as rheumatoid arthritis and chronic obstructive pulmonary disease (COPD).
- •Pts w/prior malignancies are allowed as long as they are in remission & their last treatment for such malignancy is 2 years prior to enrollment or more. Pts w/non-melanoma skin cancers that have received adequate therapy prior to enrollment & women w/history of cervical cancers are allowed.
- •Significant concurrent uncontrolled medical condition including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurologic, cerebral, or psychiatric disease.
- •Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per the investigator's assessment).
- •Adequate bone marrow function by virtue of having Platelets >50,000/ul & absolute neutrophil count (ANC) >1000/ul is required unless low counts are attributed to diffuse bone marrow infiltration with NHL as documented with a bone marrow biopsy exam.
- •Pts with creatinine >2.0 times the upper limit of normal will be excluded unless they have a normal creatinine clearance-estimated or measure 12 or 24 hour creatinine clearance of <60 mL/min
- •Pts w/total bilirubin >1.5 times upper limit of normal will be excluded, unless due to DLBCL involvement of liver or a known history of Gilbert's disease.
- •Pts with aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/Alkaline phosphatase (Alk Phos) >2.5 times upper limit of normal
- •Previous tx with Ofatumumab
- •Prior exposure to an investigational agent within 4-weeks from starting Ofatumumab
- •History of significant cerebrovascular disease or event w/significant symptoms or sequelae
- •Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to randomization, congestive heart failure (NYHA III-IV), & arrhythmia unless controlled by therapy, w/exception of extra systoles or minor conduction abnormalities.
- •Positive serology for hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive & regardless of HBsAb status, a HB DNA test will be performed and if positive the subject to be excluded. Note: If HBcAb positive and HBsAb positive, which is indicative of a past infection, subject can be included
- •Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the same sample to confirm the result.
- •Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test at screening, including women whose last menstrual period was less than 1 year prior to screening, unable or unwilling to use adequate contraception from study start to 1 year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence.
研究组 & 干预措施
Ofatumumab
The first dose administered of ofatumumab should be 300 mg to minimize infusion reactions. The initial rate of the first infusion of 1000 mg ofatumumab (0.3mg/ml) should be 12ml/h. If no infusion reactions occur the infusion rate should be increased every 30 minutes, to a maximum of 400 ml/h. If this schedule is followed, the infusion duration will be approximately 4.5 hours.
干预措施: Ofatumumab (Drug)
结局指标
主要结局
Overall Response (OR)
时间窗: evaluated every 2 months up to 80 weeks
OR = # of patients with a Complete Response (CR) plus # of patients with a Partial Response (PR) divided by the total # of evaluable patients. A CR is defined as: 1. Disappearance of all disease. 2. If nodal masses that Positron Emission Tomography (PET)- positive prior to therapy; they must be PET negative 3. If the nodal masses were Variably or PET negative; they must regress to normal. 4. No palpable liver or spleen 5. Palpable nodal masses are no longer palpable 6. Negative bone marrow biopsy A PR is defined as: 1. Regression of measurable disease and no new sites of disease. 2. \> 50% decrease in Sum of Product of Diameters (SPD) of up to 6 largest masses with no increase in the size of other nodes. If the nodal masses were PET positive prior to therapy then PET positive at previously involved sites is allowed. If they were Variably or PET negative then regression on CT is required. 3. No increase in the size of the liver or spleen
次要结局
- Overall Clinical Benefit (OCB)(Evaluated every 2 cycles (every 2 months), up to 80 weeks)
研究者
Dr. Sigrun Hallmeyer
Principal Investigator
Oncology Specialists, S.C.