A Phase 1 Open-label Study of KPT-9274 in Patients With Relapsed and Refractory Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 16
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
This study will evaluate the safety and tolerability of oral KPT-9274 for the treatment of patients with relapsed or refractory acute myeloid leukemia.
详细描述
KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory 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
- Single (Participant)
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
- •Written informed consent obtained prior to any study related procedures required solely for this research study.
- •Age ≥18 years.
- •Patients with WHO-confirmed non-APL AML who have not responded to or relapsed after at least one prior therapy and for whom no standard therapy that may provide clinical benefit is available.
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤
- •Adequate hepatic function:
- •Total bilirubin < 1.5 times the upper limit of normal (ULN) (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia], subjects with Gilbert's syndrome, total bilirubin needs to be ≤ 4 x ULN).
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN (except patients with known liver involvement of their AML who must have AST and ALT ≤ 5.0 times ULN).
- •Adequate renal function: estimated creatinine clearance of ≥ 60 mL/min, calculated using CKD-EPI Creatinine Equation (2021). https://www.kidney.org/content/ckd-epi-creatinine-equation-2021
- •Female patients of child-bearing potential must agree to use dual methods of contraception (including one highly effective and one effective method of contraception) and have a negative serum pregnancy test at Screening. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose.
- •Fertile female patients must agree to refrain from egg donation from first dose until at least 3 months following the last dose of KPT-
- •Women should not breastfeed during treatment with KPT-9724 and for 2 weeks after the last dose.
- •8. Male patients must use 2 highly effective methods of contraception if sexually active with a female of child-bearing potential, during treatment with KPT-9724, during a period of 2 weeks (5 half-lives) after the last dose of KPT-9724 plus a period of 3 months. (for 3.5 months after their last dose of KPT-9724). Fertile male patients must agree to refrain from sperm donation from first dose until at least 3.5 months following the last dose of KPT-9724.
排除标准
- •Female patients who are pregnant or lactating.
- •Radiation, chemotherapy, immunotherapy or any other anticancer therapy, including investigational anti-cancer therapy ≤ 2 weeks prior to C1D
- •Hydroxyurea is not considered an anti-cancer therapy.
- •Patients who have not recovered or stabilized (Grade 1 or to their baseline for non-hematologic toxicities) from toxicities related to their previous treatment, except for alopecia.
- •White blood cell count ≥25x109/L (hydroxyurea or leukapheresis permitted to reduce to below the exclusion criteria threshold and allow eligibility)
- •Patients with known active central nervous system (CNS) disease
- •Clinically significant severe heart disease
- •Subjects with uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment.
- •Known, active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen). Testing is not required.
- •Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea that could interfere with the absorption of KPT-
- •Serious psychiatric or medical conditions that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give consent.
研究组 & 干预措施
De-escalation Cohort; 20mg
For the purposes of dose escalation decisions, a standard 3+3 dose escalation design will be used.The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. If the MTD is exceeded at cohort 1, de-escalation to cohort 0 (20 mg) will occur. If the MTD is not exceeded in cohort 1, dose escalation will continue based on a standard 3+3 design at the dose levels.
干预措施: KPT-9274 (Drug)
Cohort 1; 30 mg
The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg.
干预措施: KPT-9274 (Drug)
Cohort 2; 40mg
Dose escalation to 40 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions.
干预措施: KPT-9274 (Drug)
Cohort 3; 60mg
Dose escalation to 60 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions.
干预措施: KPT-9274 (Drug)
Cohort 4; 80mg
Dose escalation to 80 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions.
干预措施: KPT-9274 (Drug)
Cohort 5; 100mg
Dose escalation to 100 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions.
干预措施: KPT-9274 (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: 28 days
Dose escalation will continue until the MTD is determined. The MTD is defined as the highest dose at which ≤1 patient experiences a DLT in Cycle 1. Count of participants who did not experience a DLT are listed in outcome measure data table.
次要结局
- Count of Participants Who Did Not Experience a DLT Are Listed in the Outcome Measure Data Table(28 days)