A Phase 1/Phase 2, Randomized, Open-label, Multi Cohort, Multi Center, Study Assessing the Safety, Tolerability and Preliminary Efficacy of SAR443579 a Natural Killer Cell Engager (NKCE) Targeting CD123, Administered With Different Agents in Participants With CD123 Expressing Hematological Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Sanofi
- 入组人数
- 7
- 试验地点
- 7
- 主要终点
- Number of participants with adverse events (AEs)/serious adverse events (SAEs)/adverse events of special interest (AESIs), laboratory abnormalities
研究概览
简要总结
This is a parallel, Phase 1/Phase 2, randomized, open label, multi-cohort, multi-center study assessing the safety, tolerability and preliminary efficacy of SAR443579 with different agents for treatment in adolescent and/or adult participants with CD123 expressing hematological malignancies.
This protocol is structured as a master protocol (containing common protocol elements). Individual sub-studies will explore SAR443579 with combination partners, which may include approved or investigational agents.
Experimental sub-studies will be tested through 3 parts:
Part 1: dose finding (such as dose escalation/ safety run-in). Part 2: dose optimization (when applicable). Part 3: dose expansion. In each sub-study, a dose escalation will identify preliminary recommended dose for expansion (pRDE) of SAR443579 and its respective combination partner. Following the determination of the preliminary RDE, additional participants will be enrolled in the dose expansion part, or if dose optimization needs to be further evaluated, additional participants will be enrolled in the "dose optimization/expansion" part. Dose optimization and dose expansion part could involve randomization depending on specific sub-study design.
Study will consist of a screening period, treatment period, and follow-up period.
Participants will receive study treatment until documented disease progression, unacceptable adverse events, participant's decision to stop study treatment, or completion of the maximum cycles allowed in the sub-studies, or the participant meets other criteria for discontinuation per study protocol (whichever occurs first).
详细描述
Substudy 01:
Title: A Phase 1/Phase 2, open-label, multi-center study, assessing the safety, tolerability and the preliminary efficacy of SAR443579 administered in combination with azacitidine + venetoclax in adult participants with CD123 expressing newly diagnosed Acute Myeloid Leukemia (ND-AML) that are ineligible for intensive chemotherapy
Short title: A study to investigate natural killer cell engager (SAR443579) in combination with azacitidine + venetoclax in adult participants with newly diagnosed acute myeloid leukemia
The expected duration of the study for a participant is approximately about 2.5 years. The study duration includes a screening period, an induction and maintenance. After the end of study treatment participants will enter the follow-up period for up to 2 years.
Planned number of participants:
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants with CD123-expressing hematological neoplasm per the 5th edition of the WHO Classification of Hematolymphoid Tumors.
- •Substudy 01:
- •Participants must be ≥18 years of age
- •Confirmed diagnosis of Acute Myeloid Leukemia
- •Ineligible for intensive chemotherapy. Ineligible for intensive chemotherapy is defined by the following criteria:
- •A) ≥ 75 years of age, OR
- •B) 18 to 74 years of age and meeting one or more of the following:
- •Eastern Cooperative Oncology Group (ECOG) performance status 2-
- •Cardiac history of congestive heart failure (CHF) requiring treatment or left ventricular ejection fraction (LVEF) ≤50% or symptomatic coronary heart disease confirmed by coronarography or cardiac imaging.
- •Diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% or forced expiratory volume (FEV1) ≤65%.
- •Creatinine clearance ≥30 to <45 mL/min calculated by modification of diet in renal disease (MDRD) formula.
- •Moderate hepatic impairment with total bilirubin >1.5 to ≤3.0x upper limit of normal (ULN).
- •Subject with an Eastern Cooperative Oncology Group (ECOG) performance status as follows:
- •a) 0 to 2 for participants ≥75 years of age or b) 0 to 3 for participants 18 to 74 years of age.
- •For participants ≥75 years of age, adequate renal function demonstrated by a creatinine clearance ≥30 mL/min, calculated by modification of diet in renal disease (MDRD)
- •Subject with adequate liver function demonstrated by the following:
- •For participants 18 to 74 years of age, aspartate aminotransferase (AST) ≤3.0 × ULN, alanine aminotransferase (ALT) ≤3.0 × ULN and bilirubin ≤3.0 × ULN, unless considered due to leukemic organ involvement ˂5 × ULN.
- •For participants ≥75 years of age, aspartate aminotransferase (AST) ≤3.0 × ULN, alanine aminotransferase (ALT) ≤3.0 × ULN and bilirubin ≤1.5 × ULN, unless considered due to leukemic organ involvement ˂5 × ULN.
排除标准
- •Any clinically significant, uncontrolled medical conditions (including any serious active systemic infection that is not controlled)
- •Known second malignancy either progressing or requiring active treatment within the last 3 years prior to first IMP administration
- •Known acquired immunodeficiency syndrome (AIDS-related illnesses) or HIV disease requiring antiretroviral treatment, or having active hepatitis B or C infection, or SARS-CoV-2 infection. With exception for:
- •HBV as determined by positive test for hepatitis B surface antigen (HBsAg) and/or HBV DNA. Participant who tests positive for anti-hepatitis B core (HBc) antigen IgG (with or without testing positive for anti-HBs), but tests negative for HBsAg and HBV DNA, is eligible.
- •A participant who tests positive for anti-HCV antibodies and has undetectable HCV RNA without receiving antiviral treatment for HCV is eligible.
- •Active, known, or suspected clinically significant autoimmune disease that has required systemic treatment in the past 2 years prior to first IMP administration, except controlled by replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc)
- •Predicted life expectancy ≤3 months.
- •Medical conditions requiring treatment with medications with narrow therapeutic index that are substrates of CYP enzymes and that cannot be closely monitored to allow for dose adjustment.
- •Ongoing adverse event of NCI CTCAE [Version 5.0] Grade 2 or greater severity cause by any prior anti-cancer therapy
- •Substudy 01:
- •Patient with Acute Promyelocytic Leukemia (APL)
- •Known active central nervous system involvement with AML at the time of enrollment as evidenced by cytology or pathology
- •Cardiovascular disease of New York Heart Association (NYHA) Class ≥
- •Malabsorption syndrome or other condition that precludes enteral route of administration
- •A baseline QTc interval of (using the Fridericia correction calculation) >470 msec.
- •Subject has received treatment with at least one of the following:
- •A hypomethylating agent, venetoclax and/or chemo therapeutic agent for AML other than hydroxyurea used for disease control prior to the initiation of study therapy.
- •Experimental therapies for AML.
- •Concomitant medications of strong and moderate CYP3A inducers within 7 days prior to the initiation of study treatment.
- •The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
研究组 & 干预措施
Substudy 01: SAR443579 + azacitidine + venetoclax
Part 1: Safety run-in: SAR443579 treatment will begin with an identified starting dose. Safety run-in will proceed according to the incidence of DLTs.
干预措施: SAR443579 (Biological)
Substudy 01: SAR443579 + azacitidine + venetoclax
Part 1: Safety run-in: SAR443579 treatment will begin with an identified starting dose. Safety run-in will proceed according to the incidence of DLTs.
干预措施: venetoclax (Drug)
Substudy 01: SAR443579 + azacitidine + venetoclax
Part 1: Safety run-in: SAR443579 treatment will begin with an identified starting dose. Safety run-in will proceed according to the incidence of DLTs.
干预措施: azacitidine (Drug)
结局指标
主要结局
Number of participants with adverse events (AEs)/serious adverse events (SAEs)/adverse events of special interest (AESIs), laboratory abnormalities
时间窗: Day 1 to 30 days after the last administration of study treatment
Substudy 01: Complete Remission (CR) rate (optimization part)
时间窗: Day 1 to 30 days after the last administration of study treatment
Proportion of participants who have a CR (Complete Remission) determined by the Investigator according to 2022 European Leukemia Net (ELN) recommendations for diagnosis and management of AML
Substudy 01: Complete Remission (CR) rate (expansion part)
时间窗: Day 1 up to 6 months
Proportion of participants who have a CR (Complete Remission) determined by the Investigator according to 2022 European Leukemia Net (ELN) recommendations for diagnosis and management of AML
Substudy 01: Incidence of dose limiting toxicities (DLTs) (escalation part)
时间窗: Day 1 to Day 28
次要结局
- Incidence of anti-drug anti body (ADA) against SAR443579(Day 1 to 30 days after the last administration of study treatment)
- Substudy 01: Pharmacokinetic (PK) parameter of SAR443579: Ctrough(Day 1 up to 10 cycles (each cycle 28 days))
- Substudy 01: Duration of alternative CR (expansion part)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Overall survival (expansion part)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Percentage of participants with Minimal residual disease (expansion part)(Day 1 up to 6 months)
- Substudy 01: PK parameter of venetoclax: Cmax(Day 1 to Day 28)
- Substudy 01: PK parameter of azacitidine: Cmax(Day 1 to Day 28)
- Number of participants with treatment emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs) and clinically significant laboratory abnormalities (expansion part)(Day 1 to 30 days after the last administration of study treatment)
- Substudy 01: Overall response rate (expansion part)(Day 1 up to 6 months)
- Substudy 01: Duration of CR (expansion part)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Duration of CRc (expansion part)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Composite Complete Remission (CRc) rate(Day 1 up to 6 months)
- Substudy 01: Alternative CR rate (expansion part)(Day 1 up to 6 months)
- Substudy 01: Rate of participants who are transfusion independent at baseline and remain independent during 56-day post-baseline period (all parts)(Day 1 to Day 56)
- Substudy 01: PK parameter of venetoclax: AUC(Day 1 to Day 28)
- Substudy 01: PK parameter of azacitidine: AUC(Day 1 to Day 28)
- Substudy 01: Duration of overall response (expansion part)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Event-free survival (EFS) (expansion part)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Rate of hematopoietic stem cell transplantation (HSCT) procedures immediately following study treatment administration but prior to subsequent therapy for treatment of AML (all parts)(Day 1 up to 24 months after the last administration from study treatment)
- Substudy 01: Rate of conversion from transfusion dependence to transfusion independence (all parts)(Day 1 to Day 56)
- Substudy 01: Time to treatment failure (TTF) (expansion part)(Day 1 up to 24 months after the last administration from study treatment)