First-Line Therapy With Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (GA-101) (iFCG) for Patients With Chronic Lymphocytic Leukemia (CLL) With Mutated IGHV Gene and Non-Del(17p)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 81
- 试验地点
- 1
- 主要终点
- Efficacy of the combination of ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab defined as achievement of complete remission/complete remission with incomplete marrow recovery and bone marrow minimal residual disease-negative status
研究概览
简要总结
This phase II trial studies how well ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab work in treating patients with chronic lymphocytic leukemia. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab together may work better in treating chronic lymphocytic leukemia.
详细描述
PRIMARY OBJECTIVE:
I. Estimate therapeutic activity (achievement of complete remission [CR] or CR with incomplete marrow recovery [CRi] and bone marrow minimal residual disease [MRD] negativity after 3 courses) of first-line treatment with ibrutinib, fludarabine (fludarabine phosphate), cyclophosphamide, obinutuzumab (GA101) (iFCG) in patients with chronic lymphocytic leukemia (CLL) who have mutated immunoglobulin heavy chain variable region (IGHV) and non-del(chromosome 7, p arm [17p]) fluorescence in-situ hybridization (FISH).
SECONDARY OBJECTIVES:
I. Estimate the rate of conversion of bone marrow MRD-positive after 3 courses of iFCG to bone marrow MRD-negative with 9 additional courses of ibrutinib and obinutuzumab (iG).
II. Determine the safety of this combination in the proposed patient population.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •Patients with a diagnosis of CLL/small lymphocytic lymphoma (SLL), with mutated (> 2% deviation from germ line) IGHV gene, who meet criteria to initiate first-line treatment per International Workshop on CLL Working Group (IWCLL) 2008 guidelines
- •Patients must not have received prior CLL-directed therapy
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- •Absolute neutrophil count > 500 uL
- •Platelet count > 50,000/uL
- •Serum total bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN for patients with Gilbert's disease
- •Estimated creatinine clearance >= 30 mL/min (calculated or measured by 24 hour urine collection)
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
- •Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug; women of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy; men who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug
- •Free of prior malignancies for 3 years with exception of patients diagnosed with basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast, who are eligible even if they are currently treated or have been treated and/or diagnosed in the past 2 years prior to study enrollment; if patients have another malignancy that was treated within the last 2 years, such patients can be enrolled, after consultation with the principal investigator, if the likelihood of requiring systemic therapy for this other malignancy within 2 years is less than 10%, as determined by an expert in that particular malignancy at MD Anderson Cancer Center
- •Patients or their legally authorized representative must provide written informed consent
- •Prothrombin time (PT)/international normalization ratio (INR) < 1.5 x ULN
- •Partial thromboplastin time (PTT) < 1.5 x ULN
- •Activated partial thromboplastin time (aPTT) < 1.5 x ULN
排除标准
- •Major surgery, radiotherapy, chemotherapy, biologic therapy, immunotherapy, experimental therapy within 3 weeks prior to the first dose of the study drugs and/or monoclonal antibody =< 6 weeks prior to first administration of study treatment
- •Patients with del(17p) by FISH (or known tumor protein p53 [TP53] mutation)
- •Patients with unmutated (=< 2% homology with germ line) IGHV
- •Uncontrolled active systemic infection (viral, bacterial, and fungal)
- •Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, QT prolongation or familial history of QT prolongation, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
- •History of stroke or cerebral hemorrhage within 6 months
- •Patient is pregnant or breast-feeding
- •Current or chronic hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV); subjects who are positive for hepatitis B or C core antibody or hepatitis B or C surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded; Note: Patients who are receiving intravenous immunoglobulins may become seropositive for hepatitis B antibodies; these patients are allowed on the study without additional testing
- •Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy
- •Concurrent use of investigational therapeutic agent
- •Patients may not receive other concurrent chemotherapy, radiotherapy, or immunotherapy; localized radiotherapy to an area not compromising bone marrow function does not apply
- •Malabsorption syndrome or other condition that precludes enteral route of administration
- •Concomitant use of warfarin or other vitamin K antagonists
- •Requires treatment with a strong cytochrome P450 (CYP), family 3, subfamily A (3A) inhibitor
- •Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study
- •Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia
研究组 & 干预措施
Treatment (iFCG)
See Detailed Description.
干预措施: Cyclophosphamide (Drug)
Treatment (iFCG)
See Detailed Description.
干预措施: Fludarabine Phosphate (Drug)
Treatment (iFCG)
See Detailed Description.
干预措施: Ibrutinib (Drug)
Treatment (iFCG)
See Detailed Description.
干预措施: Obinutuzumab (Biological)
结局指标
主要结局
Efficacy of the combination of ibrutinib, fludarabine phosphate, cyclophosphamide, and obinutuzumab defined as achievement of complete remission/complete remission with incomplete marrow recovery and bone marrow minimal residual disease-negative status
时间窗: After 84 days (3 cycles) of ibrutinib, fludarabine phosphate, cyclophosphamide, obinutuzumab
Simon's optimal two-stage design will be employed. The proportion of patients achieving complete remission/complete remission with incomplete marrow recovery and bone marrow minimal residual disease-negative will be estimated along with the 95% confidence interval.
次要结局
- Bone marrow minimal residual disease-negative status(After 3 cycles of ibrutinib, fludarabine phosphate, cyclophosphamide, obinutuzumab)
- Incidence of treatment emergent toxicities using a Bayesian design by Thall, Simon and Estey assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03(From the prior chemotherapy cycle to up to 84 days)
- Progression-free survival(Up to 6 years)
- Overall survival(Up to 6 years)
- Long-term incidence rate of secondary myelodysplastic syndrome/acute myeloid leukemia(Up to 6 years)
- Long-term incidence rate of Richter's transformation(Up to 6 years)
- Rate of complete remission (CR)/CR with incomplete marrow recovery (CRi) in subgroups of patients defined by fluorescence in situ hybridization (FISH) subtypes(Up to 6 years)