A Phase II Multi-center, Single Arm, Safety and Efficacy Study of MBG453 in Combination With Azacitidine and Venetoclax for the Treatment of Acute Myeloid Leukemia (AML) in Adult Patients Unfit for Chemotherapy
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 90
- 试验地点
- 41
- 主要终点
- Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only)
研究概览
简要总结
This trial seeked to extend the preliminary findings of efficacy by evaluating MBG453 in combination with hypomethylating agents (HMA) and also Bcl-2 inhibitor venetoclax.
详细描述
The primary purpose of Part 1 (Safety Run-in) was to rule out excessive toxicity of MBG453, when administered in combination with azacitidine and venetoclax.
The primary purpose of the combined Part 1 and Part 2 (Safety run-in and Expansion Part) was to evaluate efficacy of MBG453, when administered in combination with azacitidine and venetoclax in adult patients with newly diagnosed AML, who were not suitable for treatment with intensive chemotherapy.
Originally, there was an analysis planned of the complete response (CR) rate, after all subjects had completed at least 12 cycles of treatment (each cycle = 28 Days) or discontinued earlier. As Novartis decided to end the development of this compound, this primary analysis was skipped and only the final study analysis presented here. At the final analysis timepoint, there was only 1 patient who didn't completed the 12 cycles of treatment or discontinued earlier.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 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
- •Signed informed consent must be obtained prior to participation in the study.
- •Age ≥ 18 years at the date of signing the informed consent form (ICF)
- •Newly diagnosed with AML based on 2016 WHO classification (Arber et al 2016) and not suitable for intensive chemotherapy defined as: age ≥75, ECOG performance Status 2 or 3, or any of the following comomorbitities: severe cardiac comorbities (including congestive heart failure, LVEF ≤ 50%, chronic stable Angina) , pulmonary comorbidity (DLCO ≤ 65% or FEVI ≤ 65%). moderate hepatic impairment (with total Bilirubin >1.5 to 3x ULN) , renal impairment (eGFR≥ 30 ml/min/1.73m^2 to <45 ml/min/1.73m^2), or other comorbidity incompatible with intensive chemotherapy per Investigator assessement and approved by the Novartis Medical monitor)
- •Not planned for hematopoietic stem-cell transplantation (HSCT)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 , 2 or 3
排除标准
- •Prior exposure to TIM-3 directed therapy
- •History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or MGB453) or monoclonal antibodies (mAbs) and/or their excipients
- •Current use or use within 14 days prior to randomization of systemic, steroid therapy (> 10 mg/day prednisone or equivalent) or any immunosuppressive therapy. Topical, inhaled, nasal, ophthalmic steroids are allowed. Replacement therapy, steroids given in the context of a transfusion are allowed and not considered a form of systemic treatment.
- •Previous treatment at any time, with any of the following antineoplastic agents, approved or investigational; checkpoint inhibitors, venetoclax and hypomethylating agents (HMAs) such as decitabine or azacitidine.
- •Active autoimmune disease requiring systemic therapy (e.g.corticosteroids).
- •Live vaccine administered within 30 Days prior to randomization
研究组 & 干预措施
MBG453+Venetoclax +Azacitidine
Participants received MBG453 in combination with Venetoclax and Azacitidine
干预措施: MBG453 (Drug)
MBG453+Venetoclax +Azacitidine
Participants received MBG453 in combination with Venetoclax and Azacitidine
干预措施: Venetoclax (Drug)
MBG453+Venetoclax +Azacitidine
Participants received MBG453 in combination with Venetoclax and Azacitidine
干预措施: Azacitidine (Drug)
结局指标
主要结局
Incidence of Dose Limiting Toxicities (DLT)(Safety run-in Patients Only)
时间窗: From Cycle 1 Day 8 to end of Cycle 2; Cycle =28 Days
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value considered by the Investigator to be at least possibily related to MBG453 as a single contributor or in combination with other component(s) of study treatment that occurs during the DLT observation period and meets any of the criteria as per protolcol.
Percentage of Participants Achieving Complete Remission (CR) (CR Rate)
时间窗: approx. 31 months
CR rate is defined as the percentage of participants achieving a complete remission (CR) as per investigator assessment (based on IWG Cheson et al 2003, ELN 2017 Dohner et al 2017).
次要结局
- Measurable Residual Disease (MRD) - Negativity Rate: Full Study Population(approx. 31 months)
- Measurable Residual Disease (MRD) - Negativity Rate in Participants With Best Overall Response (BOR) of CR/CRi and Evaluable MRD(approx. 31 months)
- Duration of Complete Remission (CR)(approx. 31 months)
- Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Incomplete Hematologic Blood Count Recovery (CRi) (CR/CRi Rate)(approx. 31 months)
- The Duration of Complete Remission (CR)/Complete Remission With Incomplete Blood Count Recovery (CRi)(approx. 31 months)
- Percentage of Participants Achieving a Complete Remission (CR) or Complete Remission With Partial Hematologic Blood Count Recovery (CRh) (CR/CRh Rate)(approx. 31 months)
- Duration of CR/CRh(approx. 31 months)
- Event Free Survival (EFS)(approx. 31 months)
- Overall Survival (OS)(approx. 31 months)
- Peak Serum Concentration (Cmax) of MBG453(Cycle 1 Day 8 (end of infusion) and Cycle 3 Day 8 (end of infusion), cycle = 28 days)
- Trough Serum Concentration (Cmin) MBG453(Day 8 of Cycle 1,2,3,6,9,12,18, 24 and through treatment completion, an average of 24 months)
- Trough Plasma Concentration (Cmin) Venetoclax(0 hr (Pre-dose) of Day 8 of Cycle 1, 3 and 6 ; Cycle =28 days)
- Anti-drug Antibody (ADA) Prevalence at Baseline and ADA Positive Participants On-treatment(at baseline, up to 150 days after last treatment, approx. 24 months)
- Rate of Participants Who Achieved Transfusion Independence From Baseline and While on Treatment(approx. 31 months)