An Open-label, Phase 1b/2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, and Ofatumumab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Prolymphocytic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 71
- 试验地点
- 1
- 主要终点
- Percentage of Participants Achieving Response
研究概览
简要总结
The purpose of this study is to determine the efficacy and safety of a fixed-dose, daily regimen of orally administered PCI-32765 combined with ofatumumab in subjects with relapsed/refractory CLL/SLL and related diseases
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
- •Subjects with histologically confirmed chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), prolymphocytic leukemia (PLL), or Richter's transformation arising out of CLL/SLL as defined by WHO classification of hematopoietic neoplasms and satisfying ≥ 1 of the following conditions:
- •Progressive splenomegaly and/or lymphadenopathy identified by physical examination or radiographic studies
- •Anemia (<11 g/dL) or thrombocytopenia (<100,000/μL) due to bone marrow involvement
- •Presence of unintentional weight loss > 10% over the preceding 6 months
- •NCI CTCAE Grade 2 or 3 fatigue
- •Fevers > 100.5 degree or night sweats for > 2 weeks without evidence of infection
- •Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of < 6 months
- •Need for cytoreduction prior to stem cell transplant
- •Subjects must have failed ≥ 2 prior therapies for CLL including a nucleoside analog or ≥ 2 prior therapies not including nucleoside analog if there is a contraindication to such therapy
- •10% expression of CD20 on CLL/SLL cells
- •ECOG performance status ≤ 2
- •Life expectancy ≥ 12 weeks
- •Subjects must have organ and marrow function as defined below:
- •Absolute neutrophil count (ANC) ≥ 1000/µL in the absence of bone marrow involvement
- •Platelets ≥ 30,000/μL in the absence of bone marrow involvement
- •Total bilirubin ≤ 1.5 x institutional upper limit of normal unless due to Gilbert's disease
- •AST (SGOT) ≤ 2.5 x institutional upper limit of normal unless due to infiltration of the liver
- •Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min
- •No history of prior exposure to ofatumumab
- •Age ≥ 18 years
- •Body weight ≥ 40 kg
排除标准
- •A life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of PCI-32765 PO, or put the study outcomes at undue risk
- •Significant cardiovascular disease
- •Any condition which could interfere with the absorption or metabolism of PCI-32765 including unable to swallow capsules, malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
- •Known history of Human Immunodeficiency Virus (HIV) or active infection with Hepatitis C Virus (HCV) or Hepatitis B Virus (HBV) or any uncontrolled active systemic infection
- •Any anticancer immunotherapy, chemotherapy, radiotherapy, or experimental therapy within 4 weeks before first dose of study drug. Corticosteroids for disease-related symptoms are allowed provided 1 week washout occurs
- •Active central nervous system (CNS) involvement by lymphoma
- •Major surgery within 4 weeks before first dose of study drug
- •Lactating or pregnant
- •Known moderate to severe chronic obstructive pulmonary disease (COPD)
- •History of prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for at least 2 years or which will not limit survival to < 2 years
- •History of Grade ≥ 2 toxicity continuing from prior anticancer therapy including radiation
研究组 & 干预措施
Group 1
In Group 1, PCI-32765 420 mg PO was administered daily for 1 cycle (28 days) before the start of ofatumumab IV dosing
干预措施: PCI-32765 (Drug)
Group 1
In Group 1, PCI-32765 420 mg PO was administered daily for 1 cycle (28 days) before the start of ofatumumab IV dosing
干预措施: ofatumumab (Drug)
Group 2
In Group 2, PCI-32765 420 mg PO daily was initiated concomitantly with ofatumumab IV (PCI-32765 initiated on Day 2 of Cycle 1)
干预措施: PCI-32765 (Drug)
Group 2
In Group 2, PCI-32765 420 mg PO daily was initiated concomitantly with ofatumumab IV (PCI-32765 initiated on Day 2 of Cycle 1)
干预措施: ofatumumab (Drug)
Group 3
In Group 3, two cycles of ofatumumab IV were administered prior to the start of PCI-32765 420 mg PO daily
干预措施: PCI-32765 (Drug)
Group 3
In Group 3, two cycles of ofatumumab IV were administered prior to the start of PCI-32765 420 mg PO daily
干预措施: ofatumumab (Drug)
结局指标
主要结局
Percentage of Participants Achieving Response
时间窗: The median follow-up time on study for all treated participants is 12.5 (range 0.5-19.6) months
The primary endpoint for the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR), CR with incomplete blood count recovery (Cri), or partial response (PR), according to the guidelines from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL1) published in 2008 for CLL participants and International Working Group for non-Hodgkin's lymphoma (IWG NHL) 2007 criteria for SLL participants, with the modification that treatment-related lymphocytosis will not be considered progressive disease, as evaluated by the investigators. Assessment of disease is based on radiological exams, physical exam, hematological evaluations and, when appropriate, bone marrow results.
Safety During Dose-Limiting Toxicity (DLT) Observation Period
时间窗: 56 days for Group 1 and 28 days for Group 2
Number of dose-limiting toxicities observed in the first 6 participants enrolled in treatment Groups 1 and 2
次要结局
- Progression Free Survival (PFS) at 12 Months(From first dose of study treatment until disease progression, death, or until 12 months)
- Number of Participants With Treatment Emergent Adverse Events (AEs)(From first dose of study treatment to within 30 days of last dose or until study closure)