A Phase 1b/2 Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of the Selective SYK Inhibitor Lanraplenib (LANRA) in Combination With the FLT3 Inhibitor Gilteritinib, in Patients With FLT3-mutated Relapsed or Refractory AML
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Kronos Bio
- 入组人数
- 24
- 试验地点
- 17
- 主要终点
- Maximally Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of LANRA in Combination With Standard Doses of Gilteritinib
研究概览
简要总结
The primary objective of this study is to evaluate the safety of lanraplenib (LANRA) in combination with the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib, in participants with relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML).
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
- •Adults ≥18 years of age with acute myeloid leukemia (AML) and at least 1 prior line of therapy
- •FMS-like tyrosine kinase 3 (FLT3)-mutated disease documented in a local reference laboratory at the time of consideration for enrollment in the study
- •Have the ability to understand the requirements and procedures of the study and sign a written informed consent form
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2
- •Adequate hepatic and renal function
- •Prothrombin time (PT), activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation
- •Negative serum ß-human chorionic gonadotropin (HCG) test in women of child-bearing potential (WOCBP)
- •Left ventricular ejection fraction ≥50% confirmed by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan
排除标准
- •Known central nervous system (CNS) involvement with leukemia
- •Clinical signs/symptoms of leukostasis that have failed therapy including hydroxyurea and/or leukapheresis of at least 3 days duration
- •Pregnant or breastfeeding women
- •Active infection with hepatitis B, C or human immunodeficiency virus (HIV) infection
- •Disseminated intravascular coagulation with active bleeding or signs of thrombosis
- •Known active coronavirus disease 2019 (COVID-19)
- •Administration of a live attenuated virus vaccine within 35 days before Cycle 1 Day 1 (C1D1)
- •History of non-myeloid malignancy except for the following: adequately treated localized basal cell, or squamous cell carcinoma of the skin, or localized melanoma (with TNM stage either Tis [melanoma in-situ] or T1aN0M0) with complete resection; cervical carcinoma in situ; superficial bladder cancer; asymptomatic prostate cancer without known metastatic disease, with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for > 1 year prior to start of study therapy; or any other cancer that has been in complete remission without treatment for ≥3 years prior to enrollment
- •Clinically significant heart disease
- •Prolongation of the long measure between Q wave and T wave in the electrocardiogram (QT) interval at baseline
- •Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection at the time of study treatment initiation
- •Current (within 30 days of study enrollment) drug-induced liver injury, chronic active hepatitis, alcoholic liver disease, nonalcoholic steatohepatitis, primary biliary cholangitis with inadequate response to ursodeoxycholic acid or other health authority approved therapy, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension
- •Ongoing (within 6 weeks of study enrollment) hepatic encephalopathy
- •Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of leukemia
研究组 & 干预措施
LANRA 20 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 20 mg once daily (QD) as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a partial remission (PR) after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
干预措施: Lanraplenib (Drug)
LANRA 20 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 20 mg once daily (QD) as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a partial remission (PR) after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
干预措施: Gilteritinib (Drug)
LANRA 40 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 40 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
干预措施: Lanraplenib (Drug)
LANRA 40 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 40 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
干预措施: Gilteritinib (Drug)
LANRA 60 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 60 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
干预措施: Lanraplenib (Drug)
LANRA 60 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 60 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
干预措施: Gilteritinib (Drug)
LANRA 90 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 90 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
干预措施: Lanraplenib (Drug)
LANRA 90 mg QD + Gilteritinib 120 mg QD
Participants received LANRA 90 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 1. Participants also received gilteritinib 120 mg QD as oral tablets in consecutive 28-day cycles starting from Cycle 1 Day 2. Participants received treatment until progression/relapse or lack of at least a PR after 6 months of study treatment, intolerance, or withdrawal from treatment by the participant or study investigator.
干预措施: Gilteritinib (Drug)
结局指标
主要结局
Maximally Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of LANRA in Combination With Standard Doses of Gilteritinib
时间窗: Cycle 1 Day 1 to pre-dose Cycle 2 Day 1 (each cycle was 28 days)
The MTD/RP2D was defined as the highest dose with either 0 of 3 or no more than 1 of 6 patients with LANRA-related DLTs. All decisions regarding dose escalation including declaration of the MTD/RP2D were made by the dose-escalation committee (DEC).
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
时间窗: Cycle 1 Day 1 (each cycle was 28 days) to 30 days after last dose of either LANRA or gilteritinib or initiation of non-protocol antileukemic therapy, whichever was earlier (maximum duration of treatment was 183 days)
A TEAE was any unfavorable or unintended sign, symptom, laboratory abnormality or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered causally related to the study drug or not that started after the first dose of the earliest study drug through the lesser of non-protocol anti-leukemic therapy initiation or end of treatment visit. A serious TEAE was defined as any TEAE that: * Resulted in death. * Was life-threatening. * Required or prolonged a pre-existing hospitalization. * Resulted in disability/incapacity. * Was a congenital anomaly/birth defect. * Was considered a significant medical event by the investigator. TEAEs were graded for severity based on the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 as follows: * Grade 1 - Mild. * Grade 2 - Moderate. * Grade 3 - Severe. * Grade 4 - Life-threatening. * Grade 5 - Death related to adverse event (AE).
Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) for LANRA
时间窗: Cycle 1 Day 1 to pre-dose Cycle 2 Day 1 (each cycle was 28 days)
A DLT was defined as any of the following occurring within the DLT assessment period: * A nonhematologic toxicity of Grade ≥ 3 that was at least possibly related to LANRA (with noted exceptions). * Any toxicity that resulted in administration of \< 80% of the cumulative, Cycle 1 dose for either LANRA or gilteritinib. * Grade 4 neutropenia or thrombocytopenia lasting \> 28 days after treatment onset that was not attributed to active acute myeloid leukemia (AML) and was at least possibly related to LANRA. * Any toxicity that resulted in reduction in the dose of LANRA in Cycle 1. DLTs were graded for severity based on the NCI-CTCAE version 5.0 as follows: * Grade 3 - Severe. * Grade 4 - Life-threatening.
次要结局
- Tmax of Gilteritinib(Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.)
- Composite Complete Remission (cCR) Rate Per European LeukemiaNet (ELN) 2017 Criteria(Cycle 1 Day 1 until occurrence of documented CR or CRh (maximum duration of follow-up was 16.1 months).)
- Duration of Response (DOR)(From first qualifying response (CR/CRh) until relapse or death from any cause (maximum duration of follow-up was 16.1 months).)
- Maximal Plasma Concentration (Cmax) of LANRA(Cycle 1 Day 1 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.)
- Time to Cmax (Tmax) of LANRA(Cycle 1 Day 1 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.)
- Area of the Plasma Concentration x Time Curve From Hour 0 to the Last Measurable Time Point (AUC0-last) of LANRA(Cycle 1 Day 1 and Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.)
- Cmax of Gilteritinib(Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.)
- AUC0-last of Gilteritinib(Cycle 1 Day 15: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose.)
- Event-free Survival (EFS)(Cycle 1 Day 1 to treatment failure (ie, failure to achieve CR or CRh, relapse from CR/CRh or death from any cause) (maximum duration of follow-up was 16.1 months).)
- Overall Survival(Enrollment until death from any cause (maximum duration of follow-up was 16.1 months).)