A Phase 1/2, Open-label, 2-arm Study Evaluating BLU-263 as Monotherapy and in Combination With Azacitidine, in Patients With KIT Altered Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 9
- 试验地点
- 11
- 主要终点
- Dose Escalation and Expansion: Number of Participants with Serious Adverse Events (SAEs)
研究概览
简要总结
The goal of this clinical trial is to evaluate elenestinib (BLU-263) in participants with Advanced Systemic Mastocytosis (AdvSM), SM with an associated hematologic neoplasm (SM-AHN), and other hematologic malignancies. The main questions it aims to answer are:
- Determine Recommended Dose of elenestinib (BLU-263) monotherapy for participants with AdvSM
- Safety and tolerability of elenestinib (BLU-263) monotherapy
- Efficacy of elenestinib (BLU-263) monotherapy in participants with AdvSM
- Determine Recommended Dose of elenestinib (BLU-263) in combination with azacitidine in participants with AdvSM
- Safety and tolerability of elenestinib (BLU-263) in combination with azacitidine
- Efficacy of elenestinib (BLU-263) in combination with azacitidine in participants with AdvSM
The estimated study duration for each participant will be approximately 4 years: 2 years of treatment followed by 2 years of follow-up. Participants may be required to attend monthly visits for the first six months, followed by quarterly visits for the remainder of the study.
详细描述
Systemic mastocytosis includes five major subtypes: Indolent SM (ISM), SM with an associated hematologic neoplasm (SM-AHN), aggressive SM (ASM), and MC leukemia (MCL). In 2016, the smoldering subtype of SM, a former provisional ISM subvariant, was designated as a distinct variant of SM by the World Health Organization (WHO). Aggressive SM, SM-AHN, and MCL together are referred to as Advanced SM (AdvSM).
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
- 未提供
排除标准
- •Diagnosis of a Philadelphia chromosome positive malignancy
- •Acute myeloid leukemia.
- •If the participant is receiving corticosteroids, and the dose has not been stable for ≥7 days.
- •Within the 14 days prior to enrollment, participant has received any antineoplastic therapy (including midostaurin, avapritinib and other tyrosine kinase inhibitors [TKIs]) or an investigational agent.
- •Participant has received hydroxyurea within 7 days prior to the first dose of elenestinib (BLU-263).
- •Participant received prior HMA therapy (e.g., azacitidine, decitabine) for the current diagnosis.
- •Participant must not be eligible for allogenic hematopoietic stem cell transplantation.
- •Participant received prior radiotherapy within 14 days of screening BM biopsy.
- •Participant received any hematopoietic growth factor (except erythropoietin) within 14 days of screening BM biopsy, or requiring growth factors to maintain adequate neutrophil or platelet levels.
- •Those participants maintained on a chronic dose of erythropoietin, whose hemoglobin is stable, and dose of erythropoietin has not been changed in the prior 28 days are allowed on study.
- •Participant received >1 prior selective KIT inhibitor (eg: avapritinib or bezuclastinib).
- •Participant have any of the following laboratory abnormalities on last laboratory assessment within 14 days prior to the first dose of initiation of study drug: a. Alanine aminotransferase and aspartate aminotransferase > 3 × ULN; > 5 × ULN if associated with clinically suspected liver infiltration by mastocytosis or another disease for which the patient enrolled into the study b. Total bilirubin > 1.5 × ULN; > 3 × ULN if associated with liver infiltration by the disease being treated or in the presence of Gilbert's Disease. (In the case of Gilbert's disease, a direct bilirubin > 2.0 ULN would be an exclusion) c. Estimated (Cockcroft-Gault formula) or measured creatinine clearance < 40 mL/min d. Absolute neutrophil count < 0.5 × 10^9/L
- •Participant has had a major surgical procedure within 14 days of the first dose of study drug.
- •History of another primary malignancy that has been diagnosed or required therapy within 1 year prior to the first dose of study drug. The following are exempt from the 1-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, GI stromal tumor, and completely resected carcinoma in situ of any site.
- •Mean resting QTcF > 480 msec, a history of prolonged QT syndrome or Torsades de pointes, or a familial history of prolonged QT syndrome.
- •Clinically significant, uncontrolled, cardiovascular disease.
- •Arm 1 (Monotherapy):
- •Myelodysplastic Syndrome (MDS) that is very high- or high-risk as defined by the International Prognostic Scoring System for Myelodysplastic Syndromes-Revised (IPSS-R).
- •A myeloid AHN with ≥10% BM or peripheral blood blasts.
- •Platelet count <50 x 10^9/L (within 4 weeks prior to the first dose of study drug) or receiving platelet transfusions or thrombopoietin receptor agonists (TPO-RA) within the prior 14 days.
研究组 & 干预措施
Monotherapy
Participants with AdvSM (ASM, SM-AHN, or MCL) will receive BLU-263 monotherapy.
干预措施: BLU-263 (Drug)
Combination therapy
Participants with high risk and very high risk systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) of non-MC lineage will receive BLU-263 in combination with azacitidine.
干预措施: BLU-263 (Drug)
Combination therapy
Participants with high risk and very high risk systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) of non-MC lineage will receive BLU-263 in combination with azacitidine.
干预措施: Azacitidine (Drug)
结局指标
主要结局
Dose Escalation and Expansion: Number of Participants with Serious Adverse Events (SAEs)
时间窗: Up to approximately 4 years
Dose Escalation: Number of DLTs (combination therapy only)
时间窗: 28 Days
Combination therapy: The RD will be primarily determined by the number of DLTs (during 28 days starting from Day 15 of C1 or Day 15 of C2) with elenestinib (BLU-263) in combination with azacitidine.
Dose Escalation: Number of Dose-limiting Toxicities (DLTs) (monotherapy only)
时间窗: 28 Days
Monotherapy: The Recommended Dose (RD) will be primarily determined by the number of DLTs in the first 28 days of treatment with elenestinib (BLU-263) monotherapy.
Dose Escalation and Expansion: Pure Pathological Response (PPR) Rate for SM in Selective KIT Inhibitor-naïve Participants (monotherapy only)
时间窗: Up to approximately 4 years
PPR Rate is defined as complete remission (resolution of palpable splenomegaly/hepatomegaly) (CR) + complete remission with partial recovery of peripheral blood counts (CRh) + partial remission (≥35% reduction in spleen volume) (PR)
Dose Escalation and Expansion: Number of Participants with Adverse Events (AEs)
时间窗: Up to approximately 4 years
次要结局
- Dose Escalation and Dose Expansion: t1/2 of Azacitidine (combination therapy only)(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: Maximum Plasma Concentration (Cmax) of BLU-263(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: Time to Maximum Concentration (Tmax) of BLU-263(Up to approximately 4 years)
- Dose Escalation and Expansion: Overall Response Rate (ORR) for AdvSM using modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) (monotherapy only)(Up to approximately 4 years)
- Dose Escalation and Expansion: ORR for SM Using Modified IWG-MRT-ECNM (combination therapy only)(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: Cmax of Azacitidine (combination therapy only)(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: Area Under the Curve From Time Zero to 24 Hours (AUC(0-24)) of BLU-263(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: Terminal Elimination Half-life (t1/2) of BLU-263(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: CL/F of Azacitidine (combination therapy only)(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: Accumulation Ratio of BLU-263(Up to approximately 4 years)
- Dose Escalation and Expansion: Time to Response (TtR) (monotherapy only)(Up to approximately 4 years)
- Dose Escalation and Expansion: Progression-Free Survival (PFS) (monotherapy only)(Up to approximately 4 years)
- Dose Escalation and Expansion: PPR Rate for SM (combination therapy only)(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: Apparent Volume of Distribution (Vz/F) of BLU-263(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: Apparent Oral Clearance (CL/F) of BLU-263(Up to approximately 4 years)
- Dose Escalation and Expansion: Duration of Response (DOR) (monotherapy only)(Up to approximately 4 years)
- Dose Escalation and Expansion: Proportion of Participants Pursuing Stem Cell Transplant (monotherapy only)(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: Tmax of Azacitidine (combination therapy only)(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: Vz/F of Azacitidine (combination therapy only)(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: AUC(0-24) of Azacitidine (combination therapy only)(Up to approximately 4 years)
- Dose Escalation and Expansion: Overall Survival (OS) (monotherapy only)(Up to approximately 4 years)
- Dose Escalation and Dose Expansion: Accumulation Ratio of Azacitidine (combination therapy only)(Up to approximately 4 years)