An Open-label, First-in-human, Dose-escalation/Expansion Study of SAR443579 Administered as Single Agent by Intravenous Infusion in Adult and Pediatric Participants With Relapsed or Refractory Acute Myeloid Leukemia (R/R AML), B-cell Acute Lymphoblastic Leukemia (B-ALL), High Risk-myelodysplasia (HR-MDS), or Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Sanofi
- 入组人数
- 101
- 试验地点
- 46
- 主要终点
- Escalation Part: Incidence of dose-limiting toxicity (DLT)
研究概览
简要总结
This is an open-label, multicenter, Phase 1/Phase 2, dose escalation and dose expansion study to evaluate the safety, pharmacokinetics, pharmacodynamics and anti-leukemic activity of SAR443579 in various hematological malignancies.
详细描述
Study duration per participant is 2.5 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant must be at least 1 year (for France: 2 years) old at the time the trial participant or legal guardian signs the informed consent form and will be assigned as follows:
- •Adult arm: aged at least 18 years old.
- •Pediatric arm: aged 1 (for France: 2 years) to less than 18 years old.
- •Adult and Pediatric Arms: Escalation and Expansion/Optimization Cohorts A1, A2, C, D: Confirmed diagnosis of primary or secondary AML (any subtype) according to World Health Organization (WHO) 2022 classification. Participants with AML must meet one of the following criteria, a), b), c) or d) and are limited to those with no available (or are ineligible) therapy with known clinical benefit.
- •a) Primary Induction Failure (PIF) AML, defined as disease refractory to one of the following, i or ii.
- •i) An intensive induction attempt, per institution. Induction attempts include high-dose and/or standard-dose cytarabine ± an anthracyclines/anthracenedione ± an anti-metabolite, with or without growth factor or targeted therapy containing regimens.
- •ii) For adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy; PIF is defined as AML refractory to one of the following less intensive regimens, 1 or 2:
- •4 cycles of hypomethylating agents (HMA) or
- •2 cycles HMA + venetoclax b) Early relapse (ER) AML, defined as AML in relapse with CR, CRh or CRi duration less than 6 months on prior induction treatment c) Leukemia in first or higher relapse d) For participants aged 1 (for France: 2 years) to less than 18 years old, primary induction failure is defined as disease refractory after two cycles of induction therapy.
- •Adult Arm (Escalation and Expansion/Optimization Cohorts B and Japan Cohort C only): Confirmed diagnosis of MDS, meeting the following criteria:
- •intermediate or high-risk category as per a Revised International Prognostic Scoring System (IPSS-R) AND
- •confirmed CD123 + expression status determined by local institutional standards AND
- •limited to those with no available (or are ineligible) therapy with known clinical benefit.
- •Pediatric arms escalation part and Japan Cohort C only: Confirmed diagnosis of CD123+ BALL without extramedullary lesions that have no available (or are ineligible) therapy with known clinical benefit. Participants with non-CNS chloromatous disease are not allowed in the study.
- •Body weight at least 10 kg.
- •Pediatric arm and escalation part only: Confirmed diagnosis of BPDCN according to World Health Organization (WHO) 2022 classification, who have relapsed or refractory disease with no available (or are ineligible) therapy with known clinical benefit.
- •Japan participants (Cohort C): Participant must be at least 18 years old at the time the trial participant signs the informed consent form
排除标准
- •Eastern Cooperative Oncology Group (ECOG) performance status greater than 2 (at least 18 years-old). Karnofsky Scale (16 to 17 years-old) less than 50% or Lansky Scale (less than 16 years-old) less than 50%.
- •Ongoing or recent (within 5 years) evidence of significant autoimmune disease that requires or required treatment with systemic immunosuppressive treatments, which may suggest a risk for immune-related adverse events. The following are not exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that required only hormone replacement or psoriasis that does not require systemic treatment.
- •History of an invasive malignancy within the last 3 years prior to first IMP administration that requires active therapy (adjuvant hormonal therapy is allowed) other than the one treated in this study.
- •Evidence of active central nervous system leukemia at the time of enrollment as evidenced by cytology or pathology. Except for participants aged 1 (for France: 2 years) to less than 18 years, central nervous system 1 disease (CNS1) and CNS2 disease are allowed.
- •Known acquired immunodeficiency syndrome (AIDS-related illnesses) or human immunodeficiency virus (HIV) disease requiring antiretroviral treatment, or having active hepatitis B or C infection, or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
- •Prior treatment with an anti-CD123-directed agent (except for participants with BPDCN in the pediatric arm).
- •Prior HSCT with relapse beyond 3 months or prior CAR-T therapy in B-ALL with relapse beyond 2 months may be included only if off immunosuppression for a minimum of 4 weeks and no evidence of GVHD.
- •Receiving at the time of first investigational medicinal product (IMP) administration corticosteroid as a concomitant medication with corticosteroid dose more than 10 mg/day of oral prednisone or the equivalent.
- •AML, BPDCN, or HR-MDS participants with prior treatment with cellular therapy, eg, chimeric antigen receptor T cell (CAR-T) or chimeric antigen receptor NK cell (CAR-NK). Prior CAR-T therapy is allowed for participants with B-ALL.
- •Concurrent treatment with other investigational drugs.
- •Pregnant and breast-feeding women.
- •History of solid organ transplant, including corneal transplant.
- •Average QTc (using the Fridericia correction calculation) greater than 470 millisecond (msec) at screening.
- •Pediatric arm only: Participants with known inherited bone marrow failure syndromes (e.g., bloom syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome). Participants with Down syndrome with adequate organ function as per Investigator discretion are allowed to participate in the study.
- •Adult arm Expansion/Optimization- Participants with MDS evolving from a pre-existing myeloproliferative neoplasm (MPN), MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), unclassifiable MDS/MPN and therapy-related MDS (t-MDS).
- •Confirmed diagnosis of acute promyelocytic leukemia (APL) or juvenile myelomonocytic leukemia (JMML) according to WHO 2022 classification.
- •The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.
研究组 & 干预措施
SAR443579
Dose Escalation: SAR443579 administered intravenously at escalating dose levels.
Dose Expansion: SAR443579 administered intravenously at the recommended dose and schedule determined from the dose escalation.
干预措施: SAR443579 (Drug)
结局指标
主要结局
Escalation Part: Incidence of dose-limiting toxicity (DLT)
时间窗: Day 1 to Day 28
DLTs encompass both hematologic and nonhematologic toxicities, prespecified adverse reactions observed post-administration of SAR443579 and assessed by both the investigator and the sponsor.
Japan Cohort C: Incidence of DLT in Japanese participants
时间窗: Day 1 to Day 28
DLTs encompass both hematologic and nonhematologic toxicities, prespecified adverse reactions observed post-administration of SAR443579 and assessed by both the investigator and the sponsor.
Expansion/Optimization part (Cohorts A1, A2 & D), AML: Proportion of participants who have a CR + CRh + CRi according to the modified AML IWG 2003 criteria
时间窗: Up to 6 months
Measure of clinical response to treatment: Proportion of participants who have a complete remission (CR) + CR with partial hematologic recovery (CRh) + CR with incomplete hematologic recovery (CRi) according to the modified acute myeloid leukemia (AML) IWG 2003 criteria.
Expansion/Optimization part (Cohort B), MDS: Overall response rate (CR + CR equivalent + PR + CRL + CRh + HI) according to the IWG 2023 MDS response criteria
时间窗: Up to 6 months
Measure of clinical response to treatment: Overall response rate (CR + CR equivalent + partial remission (PR) + CR with limited count recovery (CRL) + CRh + hematologic improvement (HI)) according to the International Working Group (IWG) 2023 myelodysplasia (MDS) response criteria.
Dose Escalation: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Cycle 1 Day 1 up to Cycle 1 Day 28. Each cycle duration in induction period was 28 days.
The DLT was defined as any of the following events during Cycle 1 (first 28 days) using NCI CTCAE v5.0 or ASTCT criteria, whether related or not to the study treatment in the absence of clear evidence to the contrary, and if not related to disease progression. Hematologic DLTs included hematologic toxicities, bone marrow hypocellularity, decreased neutrophils lasting, febrile neutropenia, decreased platelet count lasting, anemia (all Grade 4), and Grade 3 thrombocytopenia. Non-hematologic DLTs included any Grade \>=3 toxicities except alopecia, Grade 3 fatigue, asthenia, fever, anorexia, constipation, nausea, vomiting, diarrhea, total parenteral nutrition, hospitalization related events, infection, bleeding, Grade 3 infusion related reaction and laboratory abnormalities, Grade 3 or 4 tumor lysis syndrome and isolated electrolyte abnormalities. Also, DLTs were any treatment related toxicity causing \>2 week delay in recovery to baseline/Grade \<=1 or requiring dose reduction.
Dose Escalation (Cohort C): Number of Participants With Dose Limiting Toxicities
时间窗: Cycle 1 Day 1 to Cycle 1 Day 28. Each cycle duration in induction period was 28 days.
The DLT was defined as any of the following events during Cycle 1 (first 28 days) using NCI CTCAE v5.0 or ASTCT criteria, whether related or not to the study treatment in the absence of clear evidence to the contrary, and if not related to disease progression. Hematologic DLTs included hematologic toxicities, bone marrow hypocellularity, decreased neutrophils lasting, febrile neutropenia, decreased platelet count lasting, anemia (all Grade 4), and Grade 3 thrombocytopenia. Non-hematologic DLTs included any Grade \>=3 toxicities except alopecia, Grade 3 fatigue, asthenia, fever, anorexia, constipation, nausea, vomiting, diarrhea, total parenteral nutrition, hospitalization related events, infection, bleeding, Grade 3 infusion related reaction and laboratory abnormalities, Grade 3 or 4 tumor lysis syndrome and isolated electrolyte abnormalities. Also, DLTs were any treatment related toxicity causing \>2 week delay in recovery to baseline/Grade \<=1 or requiring dose reduction.
Dose Expansion (Cohorts A1, A2 and D): Composite Complete Remission (CRc) Rate
时间窗: Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks.
The CRc rate was defined as the percentage of participants who had a response of complete remission (CR), CR with partial hematologic recovery (CRh) or CR with incomplete hematologic recovery (CRi) according to modified AML International Working Group (IWG) 2003 response criteria.
Dose Expansion (Cohort B): Overall Response Rate (ORR)
时间窗: Tumors were planned to assess on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first.
The ORR was defined as the percentage of participants who had a response of CR, CR equivalent, partial remission (PR), CR with limited count recovery (CRL), CRh or hematologic improvement (HI) according to IWG 2023 myelodysplastic syndrome (MDS) response criteria.
次要结局
- Dose Expansion (Cohorts A1, A2, B and D): Recommended Dose for Expansion (RDE)(Cycle 1 Day 1 up to Cycle 1 Day 28. Each cycle duration in induction period was 28 days.)
- Dose Escalation and Dose Expansion (Cohort A1): Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (SAEs)(From the first dose of study drug administration (Day 1) up to early termination of the study, maximum treatment duration was 117.3 weeks for dose escalation (adult), 12 weeks for dose escalation (pediatric) and 20.9 for dose expansion (Cohort A1).)
- Dose Escalation and Dose Expansion (Cohort A1): Minimum Plasma Concentration (Ctrough) of SAR443579(At Days 1, 4, 8, 11, 15, 22, and 28 of Cycle 1)
- Dose Escalation and Dose Expansion (Cohort A1): Percentage of Participants With Anti-drug Antibodies (ADA) Against SAR443579(From the first dose of study drug administration (Day 1) up to early termination of the study, maximum treatment duration was 117.3 weeks for dose escalation (adult), 12 weeks for dose escalation (pediatric) and 20.9 for dose expansion (Cohort A1).)
- Dose Escalation and Dose Expansion (Cohort C): Composite Complete Remission Rate Assessed by Acute Myeloid Leukemia 2003 Modified International Working Group Response Criteria and National Comprehensive Cancer Network (NCCN)(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapse, unacceptable AE, discontinuation or death. Maximum treatment duration: 117.3 weeks (adults) and 12 weeks (pediatrics) in dose escalation phase.)
- Dose Escalation and Dose Expansion (Cohort C): Alternative Complete Remission Rate(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapse, unacceptable AE, discontinuation or death. Maximum treatment duration: 117.3 weeks (adults) and 12 weeks (pediatrics) in dose escalation phase.)
- Dose Escalation and Dose Expansion (Cohort C): Overall Response Rate(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until relapse, unacceptable AE, discontinuation or death. Maximum treatment duration: 117.3 weeks (adults) and 12 weeks (pediatrics) in dose escalation phase.)
- Dose Expansion (Cohorts A1, A2 and D): Overall Response Rate(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks.)
- Dose Expansion (Cohorts A1, A2 and D): Duration of Composite Complete Remission Rate(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks.)
- Dose Expansion (Cohorts A1, A2, B and D): Duration of Overall Response Rate(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks.)
- Dose Expansion (Cohorts A1, A2, B and D): Alternative Complete Remission Rate(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks.)
- Dose Expansion (Cohorts A1, A2, B and D): Duration of Alternative Complete Remission Rate(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks.)
- Dose Expansion (Cohorts A1, A2, B and D): Event-Free Survival (EFS)(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks.)
- Dose Expansion (Cohorts A1, A2, B and D): Overall Survival (OS)(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks.)
- Dose Expansion (Cohorts A1, A2, B and D): Rate of Hematopoietic Stem Cell Transplantation (HSCT)(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks.)
- Dose Expansion (Cohorts A1, A2, B and D): Time to Treatment Failure (TTF)(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks.)
- Dose Expansion (Cohorts A1, A2 and D): Transfusion Independence (TI) Rate(Tumors were assessed on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first. Maximum treatment duration was 20.9 weeks.)
- Dose Expansion (Cohort B): Progression Free Survival (PFS)(Tumors were planned to assess on Day 28 of each induction cycle and Day 56 of each maintenance cycle until disease relapse, unacceptable AE, discontinuation, or death, whichever occurred first.)
- Expansion/Optimization part - Cohorts A, B and D: Recommended dose for expansion (RDE)(Up to 12 months)
- Escalation and Expansion/Optimization parts - Cohorts A, B, C and D: Number of participants with TEAEs(Up to 30 months)
- Cohorts A, B, C and D: Ctrough at Cycle 1(Cycle 1 from Day 1 to Day 28)
- Cohorts A, B, C and D: Incidence of ADA(Up to 30 months)
- Escalation and Expansion/Optimization parts - Japan Cohort C, AML: Rate of CR + CRh + CRi per AML 2003 modified IWG response criteria(Up to 6 months)
- Escalation and expansion/Optimization parts - Japan Cohort C, MDS: CR rate and ORR rate per IWG 2023 MDS response criteria for escalation part and ORR rate per IWG 2023(Up to 6 months)
- Escalation and Expansion/Optimization parts - Japan Cohort C, B-ALL: Rate of CR + CRh + CRi as defined by National Comprehensive Cancer Network (NCCN)(Up to 6 months)
- Expansion/Optimization part - Cohorts A and D: Overall response rate (ORR)(Up to 6 months)
- Expansion/Optimization part - Cohorts A and D: Duration of CR + CRh + CRi (Duration of CRc)(Up to 30 months)
- Expansion/Optimization part - Cohorts A and D: Duration of CR + CRi + CRh + PR + MLFS (Duration of overall response rate)(Up to 30 months)
- Expansion/Optimization part - Cohorts A and D: Alternative CR rate(Up to 6 months)
- Expansion/Optimization part - Cohorts A and D: Duration of CR + CRh (Duration of alternative CR)(Up to 30 months)
- Expansion/Optimization part - Cohorts A and D: Event-free survival (EFS)(Up to 6 months)
- Expansion/Optimization part - Cohorts A and D: Overall survival (OS)(Up to 30 months)
- Expansion/Optimization part - Cohorts A and D: Rate of hematopoietic stem cell transplantation (HSCT)(Up to 30 months)
- Expansion/Optimization part - Cohorts A and D: Time to treatment failure (TTF)(Up to 6 months)
- Expansion/Optimization part - Cohorts A and D: Rate of conversion from transfusion dependence(Day 0 to Day 56)
- Expansion/Optimization part - Cohorts A and D: Rate of participants who are transfusion independent at baseline and remain independent during 56-day postbaseline period(Day 0 to Day 56)
- Expansion/Optimization part - Cohort B: Alternative CR rate(Up to 6 months)
- Expansion/Optimization part - Cohort B: Duration of ORR(Up to 30 months)
- Expansion/Optimization part - Cohort B: Event-free survival (EFS)(Up to 30 months)
- Expansion/Optimization part - Cohort B: Overall survival (OS)(Up to 30 months)
- Expansion/Optimization part - Cohort B: Rate of hematopoietic stem cell transplantation (HSCT)(Up to 30 months)
- Expansion/Optimization part - Cohort B: Time to treatment failure (TTF)(Up to 30 months)
- Expansion/Optimization part - Cohort B: Duration of alternative CR (CR + CR equivalent + CRL + CRh)(Up to 30 months)
- Expansion/Optimization part - Cohort B: Progression free survival (PFS)(Up to 30 months)