A Single-arm, Open-label, Phase II Study of Sabatolimab in Combination With Azacitidine and Venetoclax in Adult Participants With High or Very High Risk Myelodysplastic Syndromes (MDS) as Per IPSS-R Criteria
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Rate of Dose Limiting Toxicities (DLTs) - All Grades (Safety run-in Patients Only)
研究概览
简要总结
The purpose of the study was to find out if the new drug sabatolimab when given in combination with azacitidine and venetoclax, was safe and had beneficial effects in participants with high or very high risk myelodysplastic syndrome (MDS) who were not suitable for treatment with intensive chemotherapy or a stem-cell transplant (HSCT).
详细描述
Approximately 76 people with high or very high risk myelodysplastic syndrome (MDS) and age ≥ 18 years were to be asked to join this study but due to the decision by Novartis to halt recruitment the study did not enroll the approximately 76 participants.
The primary purpose of Part 1 (Safety run-in) was to rule out excessive toxicity of sabatolimab, when administered in combination with azacitidine and venetoclax. The primary purpose of the combined cohort 2 of the Safety run-in (Part 1) and Expansion (Part 2) was to have evaluated efficacy of sabatolimab, when administered in combination with azacitidine and venetoclax in adult participants with high or very high risk MDS. But due to the decision by Novartis to halt recruitment at the end of the Safety run-in, the study enrolled participants in Part 1 only.
This study was to have consisted of two parts:
Safety Run-in Part:
The first approximately 18 participants to have joined the study would have been part of the safety run-in. The first approximately 6 participants would have been enrolled to the lower dose given every four weeks sabatolimab safety run-in cohort.
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 —（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)
- •Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al, 2016) by local investigator assessment with one of the following Prognostic Risk Categories, based on the revised International Prognostic Scoring System (IPSS-R) (Greenberg et al 2012):
- •Very high (> 6 points)
- •High (> 4.5-6 points)
- •Not immediately eligible for hematopoietic stem-cell transplantation (HSCT) or intensive chemotherapy at the time of screening due to individual clinical factors such as age, comorbidities and performance status, donor availability (de Witte et al 2017)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
排除标准
- •Prior exposure to TIM-3 directed therapy or any BCL-2 inhibitor (including venetoclax) at any time
- •Prior therapy with immune check point inhibitors (e.g. anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2) or cancer vaccines is not allowed if the last dose of the drug was administered within 4 months prior to start of treatment
- •Previous first-line treatment for very high risk or high risk myelodysplastic syndromes (based on IPSS-R,Greenberg et al 2012 and Arber et al, 2016) with any antineoplastic agents, approved or investigational, including for example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as decitabine or azacitidine However, a one single cycle of HMAs treatment only started prior to enrollment is allowed.
- •Live vaccine administered within 30 days prior to start of treatment
- •Current use or use within 14 days prior to start of treatment 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
- •History of severe hypersensitivity reactions to any ingredient of study drug(s) (azacitidine, venetoclax or sabatolimab) or monoclonal antibodies (mAbs) and/or their excipients
- •Participants with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al, 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 4.5
研究组 & 干预措施
sabatolimab + azacitidine + venetoclax
Part 1: Safety run-in consisted of 2 subsequent cohorts of a lower dose (cohort 1) and a higher dose (cohort 2) of sabatolimab in combination with fixed dose of venetoclax and azacitidine.
Part 2 (did not start as recruitment was stopped in Part 1) Expansion was to enroll additional participants to further investigate the regimen including sabatolimab at the higher dose, azacitidine and venetoclax. Participants data from Part 1 and Part 2 treated with the higher dose was to have been combined to determine the complete remission rate.
干预措施: sabatolimab (Drug)
sabatolimab + azacitidine + venetoclax
Part 1: Safety run-in consisted of 2 subsequent cohorts of a lower dose (cohort 1) and a higher dose (cohort 2) of sabatolimab in combination with fixed dose of venetoclax and azacitidine.
Part 2 (did not start as recruitment was stopped in Part 1) Expansion was to enroll additional participants to further investigate the regimen including sabatolimab at the higher dose, azacitidine and venetoclax. Participants data from Part 1 and Part 2 treated with the higher dose was to have been combined to determine the complete remission rate.
干预措施: azacitidine (Drug)
sabatolimab + azacitidine + venetoclax
Part 1: Safety run-in consisted of 2 subsequent cohorts of a lower dose (cohort 1) and a higher dose (cohort 2) of sabatolimab in combination with fixed dose of venetoclax and azacitidine.
Part 2 (did not start as recruitment was stopped in Part 1) Expansion was to enroll additional participants to further investigate the regimen including sabatolimab at the higher dose, azacitidine and venetoclax. Participants data from Part 1 and Part 2 treated with the higher dose was to have been combined to determine the complete remission rate.
干预措施: venetoclax (Drug)
结局指标
主要结局
Rate of Dose Limiting Toxicities (DLTs) - All Grades (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 possibly related to sabatolimab as a single contributor or in combination with other component(s) of study treatment that occurs during the DLT observation period and meets severity criteria as per protocol.
Percentage of Participants (Receiving 800mg Sabatolimab) Achieving Complete Remission (CR) Per Investigator Assessment
时间窗: up to approx. 23 months
This endpoint assessed Complete Remission (CR) Rate of participants from Cohort 2 of Part 1 and Part 2 according to Investigator assessment per modified IWG-MDS - Cheson 2006 criteria. CR is defined as follows: bone marrow blasts \<=5%, hemoglobin level ≥ 10 g/dL, platelets count ≥ 100\*10\^9/L, neutrophils count ≥ 1.0\*10\^9/L, absence of blasts in peripheral blood.
次要结局
- Trough Serum Concentration (Cmin) Sabatolimab(Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 23 months)
- Time to Complete Remission(CR)/Marrow Complete Remission (mCR)(up to approx. 23 months)
- Duration of Transfusion Independence(up to approx. 23 months)
- Duration of Complete Response (CR)/Marrow Complete Response (mCR)(up to approx. 23 months)
- Overall Survival (OS)(Date of start of treatment to date of death due to any reason, for up to approx. 23 months)
- Percentage of Subjects Achieving a Complete Remission (CR) + Morphologic Complete Remission (mCR): Safety run-in (Part 1)(up to approx. 23 months)
- Overall Response Rate (ORR) of Participants Who Achieved Hematologic Improvement (HI) or Better as Best Response(up to approx. 23 months)
- Percentage of Participants Who Are RBC/Platelets Transfusion Independent(up to approx. 23 months)
- Duration of Complete Remission (CR)(up to approx. 23 months)
- Progression-Free Survival (PFS)(up to approx. 23 months)
- Changes in Fatigue (Part 2 - Expansion)(throughout study until progressive disease, death or study discontinuation, approx. 3 years)
- Peak Serum Concentration (Cmax) of Sabatolimab(Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 23 months)
- Anti-drug Antibody (ADA) Prevalence at Baseline and ADA Incidence On-treatment by Dose Level(Continuously collected for patients during treatment with sabatolimab up to 150 days after last treatment, approx. 23 months)
- Duration of Response for Participants Who Achieved Hematologic Improvement (HI) or Better(up to approx. 23 months)
- Leukemia-Free Survival (LFS)(up to approx. 23 months)
- Event-Free Survival (EFS)(up to approx. 23 months)