A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Intravenously Administered KT-253 in Adult Patients with High Grade Myeloid Malignancies and Acute Lymphocytic Leukemia, Lymphoma, and Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 52
- 试验地点
- 11
- 主要终点
- Incidence and severity of adverse events
研究概览
简要总结
This Phase 1 study will evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD), and clinical activity of KT-253 in adult patients with relapsed or refractory (R/R) high grade myeloid malignancies, acute lymphocytic leukemia (ALL), R/R lymphoma, myelofibrosis, and R/R solid tumors. The study will identify the pharmacologically optimal dose(s) (MTD) of KT-253 as the recommended Phase 2 dose (RP2D), based on all safety, PK, PD, and efficacy data.
详细描述
This is an open-label Phase 1 (dose escalation) first-in-human study (FIH) of KT-253 in adult patients. This study will be initiated in patients with lymphomas, and solid tumors and then subsequently in patients with advanced high grade myeloid malignancies and ALL. Therefore, the study is comprised of two arms to characterize the safety and tolerability of ascending doses of KT-253 in each arm. Arm A will consist of patients with lymphomas and advanced solid tumors and Arm B will consist of patients with high grade myeloid malignancies and ALL.
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
- •All Participants:
- •Eastern Cooperative Oncology Group performance status: 0-
- •Resolved acute effects of any prior therapy except for alopecia to baseline severity or Grade ≤1 NCI CTCAE and Grade ≤2 neuropathy
- •Adequate organ function at screening
- •Solid Tumors and Lymphoma (Arm A) ONLY
- •Histologically or pathologically confirmed solid tumor or lymphoma.
- •Relapsed and/or refractory (R/R) disease to at least two prior standard-of-care treatments or tumors for whom standard therapies are not available.
- •Advanced high grade myeloid malignancies, and Acute Lymphocytic Leukemia (Arm B) ONLY • Primary diagnosis of AML, ALL, High/Very High-risk MDS, MDS/MPN. Must be relapsed/refractory to standard therapies.
排除标准
- •All Participants:
- •Ongoing unstable cardiovascular function.
- •Major surgery requiring general anesthesia within 4 weeks prior to first dose of study drug.
- •History of or active concurrent malignancy unless disease-free for ≥ 2 years.
- •Known presence of p53 mutations in tumor tissue or blood, which are known to completely inactivate p53 transcriptional activity
- •Solid Tumors and Lymphoma (Arm A) ONLY
- •Known active uncontrolled or symptomatic central nervous system (CNS) metastases.
- •Autologous or allogenic hematopoietic stem cell transplant (HSCT) within six months prior to first dose of study drug or participant has progressed within six months from the day of stem cell infusion (for lymphoma participants only).
- •Exposures to anticancer therapy or investigational therapy within 2 weeks or 5 half-lives whichever is longer prior to the first dose of study drug.
- •Received immunotherapy/biologic treatment or investigational therapy within 4 weeks prior to first dose of KT-253, including tumor vaccines and checkpoint inhibitors.
- •Advanced high grade myeloid malignancies, and Acute Lymphocytic Leukemia (Arm B) ONLY
- •Active CNS leukemia. Participants with symptoms suggestive of CNS disease will require a lumbar puncture to rule out CNS disease.
- •Prior chemotherapy/radiation (including craniospinal radiation) within 2 weeks prior to the first dose of study drug.
- •Received allogeneic hematopoietic cell transplantation (HCT) <12 weeks prior to first dose or donor lymphocyte infusion (DLI) without conditioning <4 weeks prior to first dose.
- •Received autologous stem cell transplant (ASCT) < 4 weeks prior to first dose or the patient has not recovered from transplant associated toxicities to ≤ grade 1 prior to the first dose of study drug.
- •Received chimeric antigen receptor therapy or other modified T cell therapy <3 weeks prior to the first dose.
- •Patients with signs or symptoms of Grade ≥ 2 acute or chronic graft versus host disease (GVHD) within 2 weeks of enrollment.
研究组 & 干预措施
Phase 1 Dose Escalation Arm A in patients with R/R Solid Tumors and Lymphomas
KT-253 dosed intravenous (IV) once every three weeks in 21-day cycles
干预措施: KT-253 (Drug)
Phase 1 Dose Escalation Arm B in patients with R/R High Grade Myeloid Malignancies and ALL
KT-253 dosed IV once every three weeks in 21-day cycles
干预措施: KT-253 (Drug)
结局指标
主要结局
Incidence and severity of adverse events
时间窗: From the time of signing ICF through 30 days after last dose of study drug or prior to start of a new anticancer therapy
Adverse events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0
Maximum Tolerated Dose (MTD) and recommended Phase 2 dose (RP2D) in Patients
时间窗: From the time of the first dose of study drug through 30 days after the last dose of study drug or prior to start of a new anticancer therapy
MTD and RP2D will be determined in patients with R/R high grade myeloid malignancies, ALL, and separately, in patients with lymphomas and advanced solid tumors
次要结局
- Area under the Plasma Concentration versus Time Curve (AUC) of KT-253(Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days))
- Maximum Plasma Concentration of KT-253 (Cmax)(Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days))
- Time to maximum plasma concentration of KT-253 (Tmax)(Blood samples for PK analysis collected up to Day15 during cycle 1 and cycle 2 (each cycle is 21 days))
- Evidence of Clinical Activity of KT-253 in AML patients(From the time of the first dose of study drug through 30 days after the last dose of study drug or until disease recurrence or death, whichever occurs first, about 18 months)
- Evidence of Clinical Activity of KT-253 in ALL patients(From the time of the first dose of study drug through 30 days after the last dose of study drug or until disease recurrence or death, whichever occurs first, about 18 months)
- Evidence of Clinical Activity of KT-253 in High/Very High-Risk Myelodysplastic syndromes (MDS) patients(From the time of the first dose of study drug through 30 days after the last dose of study drug or until disease recurrence or death, whichever occurs first, about 18 months)
- Evidence of Clinical Activity of KT-253 in MDS/ Myeloproliferative Neoplasms (MPN) patients(From the time of the first dose of study drug through 30 days after the last dose of study drug or until disease recurrence or death, whichever occurs first, about 18 months)
- Evidence of Clinical Activity of KT-253 in R/R Lymphoma patients(From Baseline scan until first documented progression or death from any cause, whichever comes first , about 18 months)
- Evidence of Clinical Activity of KT-253 in R/R Solid Tumor patients(From Baseline scan until first documented progression or death from any cause, whichever comes first, about 18 months)
- Duration of Response (DoR) in Patients Treated with KT-253(From date of first of response to the date of documented first progression or death whichever comes first, about 18 months)