A Phase Ib/II, Open Label, Proof-of-concept Study of Sabatolimab and Magrolimab-based Therapy for Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Percentage of participants achieving complete remission (CR) according to Investigator assessment per treatment arm
研究概览
简要总结
This study is to determine the safety and preliminary efficacy of sabatolimab in combination with magrolimab and azacitidine in adult participants with 1L unfit Acute Myeloid Leukemia (AML) or with 1L higher risk Myelodysplastic Syndromes (MDS), and sabatolimab in combination with magrolimab in participants with relapsed or refractory (R/R) AML.
详细描述
The primary purpose of the Safety run-in is to rule out excessive toxicity and investigate safety of the combination of sabatolimab with azacitidine and magrolimab in previously untreated participants with higher-risk MDS and unfit AML. The primary purpose of the combined Safety Run-in and Expansion is to assess the preliminary efficacy of the combination of sabatolimab with magrolimab with (cohort 1 and 2) or without (cohort 3) azacitidine in terms of achieving complete remission in 3 different indications:
- Previously untreated participants with AML, who are unfit for intensive chemotherapy (1L unfit AML - cohort 1),
- Previously untreated participants with higher-risk MDS (1L higher risk MDS - cohort 2),
- Participants with R/R AML after having been previously treated with only first line venetoclax in combination with hypomethylating agent (VEN+HMA) (R/R AML - cohort 3).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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)
- •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 comorbidities: severe cardiac comorbidity (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 30 ml/min/1.73m^2), or other comorbidity incompatible with intensive chemotherapy per Investigator assessment and approved by the Novartis Medical monitor) OR
- •Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber et al 2016), that is intermediate, high or very high risk (higher risk) based on the revised International Prognostic Scoring System (IPSS-R) (Greenberg et al 2012), previously untreated for higher risk MDS [1L higher risk MDS]:
- •Intermediate (>3-4.5 points)
- •High (> 4.5-6 points)
- •Very high (> 6 points) OR (for expansion only) Participants with AML relapsed or refractory to venetoclax in combination with a hypomethylating agent (VEN+HMA) as defined by failure to achieve bone marrow blast <5% after at least 2 cycles of VEN+HMA (refractory) or relapsed after having achieved BM blast <5% following previous treatment with VEN+HMA as first and the only line of treatment for AML
- •Eastern Cooperative Oncology Group (ECOG) performance status must be 0-2 for participants ≥ 75 years of age, OR 0-3 for participants < 75 years of age
- •White blood cell (WBC) count ≤ 20 x 10^3/μL prior to first dose of study treatment (may be reduced with leukapheresis, hydroxyurea, or oral etoposide)
- •Hemoglobin ≥ 9 g/dL prior to initial dose of study treatment. Transfusions are allowed to meet hemoglobin eligibility prior to first dose of study treatment
排除标准
- •Prior treatment with CD47 or signal regulatory protein alpha (SIRPα) targeting agents
- •Prior exposure to TIM-3 directed therapy
- •Prior therapy with immune checkpoint inhibitors (eg, anti-CTLA4, anti-PD-1, anti-PDL1, 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 the study treatment
- •For participants with higher risk MDS only: Previous first-line treatment for intermediate, high, very high risk (higher risk) MDS (based on IPSS-R) with any antineoplastic agents including for example chemotherapy and hypomethylating agents such as decitabine or azacitidine.
- •For participants with newly diagnosed AML only: Previous treatment at any time, with any approved or investigational antineoplastic agents for AML or higher risk MDS.
- •Prior and concurrent therapy with hydroxyurea or oral etoposide (to reduce WBC count), supportive care ruxolitinib, erythroid and/or myeloid growth factors are allowed.
- •Acute promyelocytic leukemia
- •Known inherited or acquired bleeding disorders
- •Patients with CNS leukemia or neurologic signs and symptoms suggestive of CNS leukemia (unless CNS leukemia had been excluded)
- •Other protocol defined inclusion/exclusion criteria may apply
研究组 & 干预措施
1L higher risk MDS
Participants with 1L MDS will receive sabatolimab and magrolimab in combination with azacitidine
干预措施: Sabatolimab (Drug)
1L higher risk MDS
Participants with 1L MDS will receive sabatolimab and magrolimab in combination with azacitidine
干预措施: Magrolimab (Drug)
1L higher risk MDS
Participants with 1L MDS will receive sabatolimab and magrolimab in combination with azacitidine
干预措施: Azacitidine (Drug)
1L unfit AML
Participants with 1L AML unfit for intensive chemotherapy will receive sabatolimab and magrolimab in combination with azacitidine
干预措施: Sabatolimab (Drug)
1L unfit AML
Participants with 1L AML unfit for intensive chemotherapy will receive sabatolimab and magrolimab in combination with azacitidine
干预措施: Magrolimab (Drug)
1L unfit AML
Participants with 1L AML unfit for intensive chemotherapy will receive sabatolimab and magrolimab in combination with azacitidine
干预措施: Azacitidine (Drug)
Relapsed/refractory AML previously treated with venetoclax and azacitidine
Participant with relapsed/refractory AML will receive sabatolimab and magrolimab (in absence of complete response (CR), Complete Remission with incomplete hematologic recovery (CRi) or Morphologic Leukemia-Free State (MLFS) after 2 cycles, participants will be allowed to also receive azacitidine)
干预措施: Sabatolimab (Drug)
Relapsed/refractory AML previously treated with venetoclax and azacitidine
Participant with relapsed/refractory AML will receive sabatolimab and magrolimab (in absence of complete response (CR), Complete Remission with incomplete hematologic recovery (CRi) or Morphologic Leukemia-Free State (MLFS) after 2 cycles, participants will be allowed to also receive azacitidine)
干预措施: Magrolimab (Drug)
结局指标
主要结局
Percentage of participants achieving complete remission (CR) according to Investigator assessment per treatment arm
时间窗: Up to 4 years from last patient first treatment
Assessing the Complete Remission (CR) Rate in each treatment arm (including participants from safety run-in and expansion) per IWG -Cheson 2003 and ELN AML recommendations - Doehner 2017 (AML) and per modified IWG-MDS criteria- Cheson 2006 (MDS) in each treatment arm.
Percentage of participants with dose limiting toxicities (only for participants enrolled in the safety run-in part)
时间窗: Cycle 1 Day 1 to the end of Cycle 2 (up to 14 days from the planned cycle 3 Day 1) ; Cycle = 28 Days
Assessment of tolerability of sabatolimab and magrolimab given together with azacitidine
次要结局
- Anti-drug-antibody prevalence on treatment(Throughout study until 90 day safety follow up for sabatolimab and 30 day safety follow up for magrolimab)
- Peak of Serum Concentration (Cmax) sabatolimab and magrolimab(Day 1 of week 2, 5, 13 for sabatolimab. Day 1 or week 1, 5, 13 for magrolimab)
- Trough serum concentration (Cmin) sabatolimab(Day 1 of week 2, 5, 9, 13, 25, 37, 49, 73, 97, end of treatment (EOT) (within 7 days after the last dose of study treatment), 30 days after last dose of sabatolimab, and 90 days after the last dose of sabatolimab for sabatolimab)
- Anti-drug-antibody prevalence at baseline(prior to first dose of sabatolimab on week 2 Day 1 and first dose of magrolimab on week 1 day 1)
- Trough serum concentration (Cmin) magrolimab(Day 1 or week 1, 2, 5, 9, 13, 25, 37, 49, 73, 97, end of treatment (EOT) (within 7 days after the last dose of study treatment), 30 days after last dose of magrolimab for magrolimab)
- Time from first occurrence of CR (complete remission) to relapse from CR or death due to any cause whichever occurs first (All 3 arms)(Up to 4 years from last patient first treatment)
- Percentage of participants achieving CR, CR with incomplete hematologic recovery (CRi), or partial response (PR) as per Investigator (1L unfit AML and R/R AML arms only)(Up to 4 years from last patient first treatment)
- Percentage of participants achieving CR or CRi (1L unfit AML and R/R AML arms only)(Up to 4 years from last patient first treatment)
- Percentage of participants achieving CR or CRh (1L unfit AML and R/R AML arms only)(Up to 4 years from last patient first treatment)
- Percentage of participants achieving CR with Measurable Residual Disease (MRD)-negative status(1L unfit AML and R/R AML arms only)(Up to Day 1 of cycle 13 ; Cycle=28 days)
- Percentage of participants achieving CR or CRi with MRD-negative status (1L unfit AML and R/R AML arms only)(Up to Day 1 of Cycle 13 ; Cycle =28 days)
- Percentage of participants achieving CR, marrow CR (mCR), partial response (PR), hematologic improvement (HI) per Investigator assessment (1L higher risk MDS arm only)(Up to 4 years from last patient first treatment)
- Percentage of participants who are red blood cells (RBC)/platelets transfusion independent (1L MDS arm only)(From start of treatment up to until 4 years after last patient first treatment)
- Duration of transfusion independence (1L MDS arm only)(From start of treatment up to until 4 years after last patient first treatment)