Phase Ib Open-label Study of VAY736 and Ibrutinib in Patients With Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 39
- 试验地点
- 5
- 主要终点
- Dose Intensity of Ibrutinib
研究概览
简要总结
Patients enrolled to the study had chronic lymphocytic leukemia (CLL) and received ibrutinib. Patients had either received ibrutinib for one year without having had a complete response or patients developed a resistance mutation to ibrutinib. This study had two parts, a dose escalation part and a dose expansion part.
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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of CLL per the WHO classification
- •At least 18 years of age
- •Lack of a complete response after receiving ibrutinib for > 1 year OR presence of known ibrutinib resistance mutation
- •Actively receiving ibrutinib at either 420 mg (patients enrolled to the escalation arm) or at a stable dose for at least 2 months prior to starting study treatment (patients enrolled to the expansion arm)
排除标准
- •Known history of HIV
- •Active hepatitis B or C infection
- •Receipt of attenuated vaccine within 2 weeks prior to starting study treatment.
研究组 & 干预措施
Dose Escalation
Increasing doses of VAY736 in combination with a fixed dose of ibrutinib.
干预措施: VAY736 (Drug)
Dose Escalation
Increasing doses of VAY736 in combination with a fixed dose of ibrutinib.
干预措施: ibrutinib (Drug)
Dose expansion
Evaluation of the MTD/RD of the combination of VAY736 and ibrutinib that was identified in dose escalation.
干预措施: VAY736 (Drug)
Dose expansion
Evaluation of the MTD/RD of the combination of VAY736 and ibrutinib that was identified in dose escalation.
干预措施: ibrutinib (Drug)
结局指标
主要结局
Dose Intensity of Ibrutinib
时间窗: Up to 8.5 months
Dose intensity of ibrutinib was calculated as: Actual Cumulative dose (mg) / (Duration of exposure in days)
Number of Participants With Dose-Limiting Toxicities (DLTs) in Cycle 1 (Escalation Only)
时间窗: 28 days
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications that occurs within the first 28 days of treatment with the combination of VAY736 and ibrutinib and meets the criteria defined in the study protocol. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: From first dose of study treatment up to 30 days after the last dose of VAY736, up to approximately 8.8 months
Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE. All patients were followed for a 30-day safety follow-up period subsequent to completion of VAY736 therapy. No new AEs or SAEs were collected beyond the 30-day safety follow-up or during the efficacy follow up period.
Number of Participants With Dose Reductions and Dose Interruptions of VAY736
时间窗: Up to 7.8 months
For patients who did not tolerate the protocol-specified dosing schedule of the study drugs, dose adjustments could be permitted in order to allow the patient to continue study treatment.
Number of Participants With Dose Reductions and Dose Interruptions of Ibrutinib
时间窗: Up to 8.5 months
For patients who did not tolerate the protocol-specified dosing schedule of the study drugs, dose adjustments could be permitted in order to allow the patient to continue study treatment.
Dose Intensity of VAY736
时间窗: Up to 7.8 months
Dose intensity of VAY736 was calculated as: Actual Cumulative dose (mg/kg) / (Duration of exposure in weeks/2)
次要结局
- CR or CRi Rate at C9 for Expansion Arm A and Arm B by Investigator Per IWCLL(Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.)
- Posterior Mean of CR or CRi Response Rate at C9 for Expansion Arm A and Arm B (Bayesian Analysis)(Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.)
- Posterior Probability That the True CR or CRi Response Rate at C9 for Expansion Arm A and Arm B Falls in Pre-defined Activity Intervals (Bayesian Analysis)(Cycle 9 Day 1 (C9). The duration of each cycle was 28 days.)
- Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Escalation Part(Up to approximately 2.5 years)
- Overall Response Rate (ORR) Assessed by Investigator Per IWCLL in the Dose Expansion Part(Up to approximately 2.7 years)
- Time to Progression (TTP) in the Dose Escalation Part(Up to approximately 2.5 years)
- Time to Progression (TTP) in the Dose Expansion Part(Up to approximately 2.7 years)
- Percentage of Participants With Clearance of Ibrutinib Resistance Mutation During Treatment (up to C9) for Expansion Arm B(Up to Cycle 9 Day 1. The duration of each cycle was 28 days.)
- Maximum Observed Serum Concentration (Cmax) of VAY736(Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days)
- Time to Reach Maximum Serum Concentration (Tmax) of VAY736(Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days)
- Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of VAY736(Pre-infusion and 2, 6, 24, 72, 168 and 336 hours after end of infusion on Cycle 1 Day 1 and Cycle 3 Day 1. The duration of the infusion was approximately 2 hours. 1 cycle=28 days)
- Maximum Observed Plasma Concentration (Cmax) of Ibrutinib(Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days)
- Time to Reach Maximum Plasma Concentration (Tmax) of Ibrutinib(Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days)
- Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Ibrutinib(Pre-dose and 0.5, 2, 6 and 24 hours post-dose on Cycle 1 Day 1 and Cycle 1 Day 8. 1 cycle=28 days)
- Number of Participants With Anti-VAY736 Antibodies(Baseline (before first dose) and post-baseline (assessed throughout the VAY736 treatment, up to 7.8 months).)