A Phase 2 Open-Label Study of the Efficacy of ABT-199 (GDC-0199) in Subjects With Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia Harboring the 17p Deletion
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 158
- 试验地点
- 48
- 主要终点
- Overall Response Rate (Main Cohort)
研究概览
简要总结
This was an open-label, multicenter, global study to determine the efficacy of ABT-199 (Venetoclax) monotherapy in participants with relapsed/refractory (R/R) or previously untreated chronic lymphocytic leukemia (CLL) harboring 17p deletion.
详细描述
This study was designed to enroll approximately 150 participants in 2 cohorts: a main cohort of approximately 100 participants, and a safety expansion (SE) cohort of approximately 50 participants. The primary objective of the main cohort was to evaluate the efficacy of ABT-199 monotherapy in participants with R/R CLL harboring the 17p deletion. The primary objective of the safety expansion cohort was to evaluate the safety of ABT-199 in approximately 50 participants with R/R CLL harboring 17p deletion treated per updated tumor lysis syndrome (TLS) prophylaxis and management measures.
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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant must be greater than or equal to 18 years of age.
- •Participant must have diagnosis of chronic lymphocytic leukemia (CLL) that meets published 2008 Modified IWCLL NCI-WG (International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group) Guidelines.
- •Participant has an indication for treatment according to the 2008 Modified IWCLL NCI WG Guidelines;
- •Participant has clinically measurable disease (lymphocytosis > 5 × 10^9/L and/or palpable and measurable nodes by physical exam and/or organomegaly assessed by physical exam);
- •Participant must be refractory or have relapsed after receiving at least one prior line of therapy (participants that have progressed after 1 cycle of treatment or have completed at least 2 cycles of treatment for a given line of therapy) or previously untreated CLL (previously untreated CLL participants must have received no prior chemotherapy or immunotherapy. Participants with a history of emergency, loco-regional radiotherapy (e.g., for relief of compressive signs or symptoms) are eligible. In addition, participants must meet the CLL diagnostic criteria above and must have > 5 × 10^9/L B-Lymphocytes in the peripheral blood.);
- •Participants must have 17p deletion, assessed by local laboratory (in bone marrow or peripheral blood) or assessed by central laboratory (peripheral blood).
- •Participant has an Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to
- •Participant must have adequate bone marrow function at Screening as follows:
- •Absolute Neutrophil Count (ANC) greater than or equal to 1000/µL, or
- •For subjects with an ANC less than 1000/µL at Screening and bone marrow heavily infiltrated with underlying disease (unless cytopenia is clearly due to marrow involvement of CLL), growth factor support may be administered after Screening and prior to the first dose of ABT-199 to achieve the ANC eligibility criteria (greater than or equal to 1000/µL);
- •Platelets greater than 30,000/mm^3 (without transfusion support within 14 days of Screening, without evidence of mucosal bleeding, without known history of bleeding episode within 3 months of Screening, and without history of bleeding disorder);
- •Hemoglobin greater than or equal to 8.0 g/dL.
- •Participant must have adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening as follows:
- •Activated partial thromboplastin time (aPTT) and prothrombin time (PT) not to exceed 1.5 × the upper limit of normal;
- •Calculated creatinine clearance greater than 50 mL/min using 24-hour Creatinine Clearance or modified Cockcroft-Gault equation (using Ideal Body Mass [IBM] instead of Mass). For participants that have body mass index (BMI) of > 30 kg/m^2 or < 19 kg/m^2, 24-hour measured urine creatinine clearance is required;
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3.0 × the upper normal limit of institution's normal range; Bilirubin less than or equal to 1.5 × upper limit of normal. Participants with Gilbert's Syndrome may have a bilirubin greater 1.5 × upper limit of normal, per correspondence between the investigator and AbbVie medical monitor.
- •For participants at high risk of tumor lysis syndrome a pre-approval by the AbbVie medical monitor is required prior to enrollment.
排除标准
- •Participant has undergone an allogeneic stem cell transplant.
- •Participant has developed Richter's transformation confirmed by biopsy.
- •Participant has prolymphocytic leukemia.
- •Participant has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to Screening), including autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura despite low dose corticosteroids.
- •Participant has previously received ABT-
- •Participant has received a biologic agent for anti-neoplastic intent within 30 days prior to the first dose of study drug.
- •Participant has received any of the following within 14 days or 5 half-lives as applicable prior to the first dose of study drug, or has not recovered to less than Common Toxicity Criteria (CTC) grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy:
- •Any anti-cancer therapy including chemotherapy, or radiotherapy;
- •Investigational therapy, including targeted small molecule agents.
- •Participant has known allergy to both xanthine oxidase inhibitors and rasburicase.
研究组 & 干预措施
Main Cohort
Participants received ABT-199 tablets once daily (QD) orally for up to 79 months. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
干预措施: ABT-199 (Main Cohort) (Drug)
Safety Expansion Cohort
Participants received ABT-199 tablets once daily (QD) orally for up to 68 months. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg.
干预措施: ABT-199 (Safety Expansion Cohort) (Drug)
结局指标
主要结局
Overall Response Rate (Main Cohort)
时间窗: Up to 36 weeks
The overall response rate (ORR) is defined as the proportion of participants with an overall response (complete remission \[CR\] + complete remission with incomplete marrow recovery \[CRi\] + nodular partial remission \[nPR\] + partial remission \[PR\]) per the 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (IWCLL)/National Cancer Institute-Working Group (NCI-CWG) criteria as assessed by the Independent Review Committee (IRC) in the first 70 participants treated in the Main Cohort.
Number of Participants With Adverse Events (Safety Expansion Cohort)
时间窗: From the first dose of study drug until 30 days following last dose of study drug (up to 69 months)
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study drug. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.
次要结局
- Duration of Overall Response(Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up)
- Progression-free Survival(Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up)
- Event-free Survival(Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up)
- Time to Progression(Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up)
- Time to First Response(Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up)
- Time to 50% Reduction in Absolute Lymphocyte Count(Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up)
- Overall Survival(Up to the data cutoff date of 15 December 2020, approximately 7.5 years of follow-up)
- Percentage of Participants Who Moved on to Stem Cell Transplant(Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up)
- Overall Response Rate (ORR) (Safety Expansion Cohort)(Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up)
- Complete Remission (CR) Rate(Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up)
- Partial Remission (PR) Rate(Up to the data cutoff date of 15 June 2017, approximately 4 years of follow-up)