An Investigator Sponsored Phase I Trial of Selinexor (KPT-330) Plus FLAG-Ida for the Treatment of Relapsing/Refractory AML
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 16
- 试验地点
- 4
- 主要终点
- Find recommended phase 2 dose
研究概览
简要总结
This protocol corresponds to a multicenter, open-label, non-randomized, phase I study designed to determine the safety of the combination of selinexor with chemotherapy in young patients with relapsed or refractory AML.
The clinical trial is divided into pre-treatment, treatment (induction and consolidation cycles) and follow-up periods and consists of a phase I design in which es-calating doses of selinexor will be given to 3 groups, each with 3-6 patients until achieving the maximum tolerated dose (MTD).
详细描述
Study Design:
This protocol corresponds to a multicenter, open-label, non-randomized, phase I study designed to determine the safety of the combination of selinexor with chemotherapy in young patients with relapsed or refractory AML.
The clinical trial is divided into pre-treatment, treatment (induction and consolidation cycles) and follow-up periods and consists of a phase I design in which es-calating doses of selinexor will be given to 3 groups, each with 3-6 patients until achieving the maximum tolerated dose (MTD).
Each cycle (second induction, consolidation or maintenance) of treatment will compromise 3 weeks of selinexor treatment, and at least one week off treatment. The new cycle will not start if there is an ongoing grade 3 or higher non-hematologic toxicity or persistent grade 3 neutropenia in patients achieving CR.
Study design allows a maximum of 18 patients.
研究设计
- 研究类型
- Interventional
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent in accordance with national, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure.
- •Age ≥ 18, and ≤ 65 years old.
- •Eastern Cooperative Oncology Group (ECOG) performance status of ≤
- •Diagnosis of AML (defined using WHO criteria) of any type except for acute promyelocytic leukemia (APL; AML M3).
- •Relapsing or refractory AML, defined as either:
- •Recurrence of disease after first CR (duration of CR ≤ 24 months), or Failure to achieve CR or CRi after 1 or 2 identical induction cycles containing an anthracycline plus cytarabine based schedule.
- •No contraindications to receive intensive chemotherapy.
- •Female patients of child-bearing potential must have a negative serum pregnancy test at screening and agree to use two reliable methods of contraception for three months after their last dose of medication. Male patients must use a reliable method of contraception (if sexually active with a female of child-bearing potential).
- •Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.
排除标准
- •Patients with APL/AML M
- •Patients who are pregnant or lactating.
- •Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤ 2 weeks prior to Cycle 1 Day 1 or radio-immunotherapy 4 weeks prior to Cycle 1 Day
- •Hydroxyurea is permitted until 1 day prior to Cycle 1 Day
- •Previous treatment with a SINE compound.
- •Major surgery within 2 weeks of first dose of study drug.
- •Any life-threatening illness, medical condition or organ system dysfunction which, in the Investigator's opinion, could compromise the patient's safety.
- •Unstable cardiovascular function:
- •Symptomatic ischemia, or uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on anti-arrhythmia are excluded; 1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or congestive heart failure (CHF) of NYHA Class ≥ 3, or myocardial infarction (MI) within 3 months.
- •Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral.
- •Active hepatitis B or hepatitis C infection.
- •Known human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study).
- •Patients unable to swallow tablets, patients with malabsorption syndrome, or any other gastrointestinal (GI) disease or GI dysfunction that could interfere with absorption of study treatment.
- •Any of the following laboratory abnormalities unless due to leukemia:
- •Hepatic dysfunction: bilirubin > 2.0 times the upper limit of normal (ULN) (except patients with Gilbert's syndrome: total bilirubin of > 3 x ULN) and alanine aminotransferase (ALT) and aspartic aminotransferase (AST) > 2.5 times ULN or in case of liver metastases: In patients with known liver involvement of their cancer, AST and ALT > 5 x ULN.
- •Severe renal dysfunction: estimated creatinine clearance of < 30 mL/min, measured in 24 hour urine or calculated using the formula of Cockroft and Gault: (140-Age) x Mass (kg)/[72 x creatinine (mg/dL)]; multiply by 0.85 if female
研究组 & 干预措施
Fludarabine-Idarubicine-Cytarabine- Selinexor
fludarabine 30 mg/m2/day intravenously on days 1 to 4, idarubicin 10 mg/m2/day intravenously on days 1 to 3, cytarabine 2 g/m2/day intravenously on days 1 to 4, G-CSF 300 mcg/m2/day subcutaneously from days -1 to 5. This schedule will be combined with oral selinexor (KPT-330) for three weeks at days and dose according to escalation level:
- Level -1: Selinexor 40 mg/day, once weekly
- Level 1: Selinexor 60 mg/day, once weekly
- Level 2: Selinexor 80 mg/day, once weekly
- Level 3: Selinexor 100 mg/day, once weekly
干预措施: Selinexor (Drug)
Fludarabine-Idarubicine-Cytarabine- Selinexor
fludarabine 30 mg/m2/day intravenously on days 1 to 4, idarubicin 10 mg/m2/day intravenously on days 1 to 3, cytarabine 2 g/m2/day intravenously on days 1 to 4, G-CSF 300 mcg/m2/day subcutaneously from days -1 to 5. This schedule will be combined with oral selinexor (KPT-330) for three weeks at days and dose according to escalation level:
- Level -1: Selinexor 40 mg/day, once weekly
- Level 1: Selinexor 60 mg/day, once weekly
- Level 2: Selinexor 80 mg/day, once weekly
- Level 3: Selinexor 100 mg/day, once weekly
干预措施: fludarabine (Drug)
Fludarabine-Idarubicine-Cytarabine- Selinexor
fludarabine 30 mg/m2/day intravenously on days 1 to 4, idarubicin 10 mg/m2/day intravenously on days 1 to 3, cytarabine 2 g/m2/day intravenously on days 1 to 4, G-CSF 300 mcg/m2/day subcutaneously from days -1 to 5. This schedule will be combined with oral selinexor (KPT-330) for three weeks at days and dose according to escalation level:
- Level -1: Selinexor 40 mg/day, once weekly
- Level 1: Selinexor 60 mg/day, once weekly
- Level 2: Selinexor 80 mg/day, once weekly
- Level 3: Selinexor 100 mg/day, once weekly
干预措施: idarubicin (Drug)
Fludarabine-Idarubicine-Cytarabine- Selinexor
fludarabine 30 mg/m2/day intravenously on days 1 to 4, idarubicin 10 mg/m2/day intravenously on days 1 to 3, cytarabine 2 g/m2/day intravenously on days 1 to 4, G-CSF 300 mcg/m2/day subcutaneously from days -1 to 5. This schedule will be combined with oral selinexor (KPT-330) for three weeks at days and dose according to escalation level:
- Level -1: Selinexor 40 mg/day, once weekly
- Level 1: Selinexor 60 mg/day, once weekly
- Level 2: Selinexor 80 mg/day, once weekly
- Level 3: Selinexor 100 mg/day, once weekly
干预措施: cytarabine (Drug)
Fludarabine-Idarubicine-Cytarabine- Selinexor
fludarabine 30 mg/m2/day intravenously on days 1 to 4, idarubicin 10 mg/m2/day intravenously on days 1 to 3, cytarabine 2 g/m2/day intravenously on days 1 to 4, G-CSF 300 mcg/m2/day subcutaneously from days -1 to 5. This schedule will be combined with oral selinexor (KPT-330) for three weeks at days and dose according to escalation level:
- Level -1: Selinexor 40 mg/day, once weekly
- Level 1: Selinexor 60 mg/day, once weekly
- Level 2: Selinexor 80 mg/day, once weekly
- Level 3: Selinexor 100 mg/day, once weekly
干预措施: G-CSF (Drug)
结局指标
主要结局
Find recommended phase 2 dose
时间窗: 3 months
A standard 3 + 3 dose escalation schedule will be used for all escalations. Initially, three patients will be entered in each cohort at the scheduled starting dose level for that cohort. If a drug-related DLT (see Section 5.1.5.3) is not seen at the scheduled dose, the dose will be escalated for the subsequent group of 3 patients. If 1 of 3 patients experiences a drug-related DLT, then 3 additional patients will receive that dose. If ≤ 2 of 6 patients experiences a drug-related DLT, the next scheduled dose level will be available. If, at a given dose level, \> 2 patients experience a drug-related DLT, the MTD will have been exceeded, additional enrollment within that cohort will cease, and dose escalation will stop. If a dose level proves intolerable (≥ 3 patients experience a DLT), enrollment will proceed at one dose-level lower.
Maximum tolerated dose (MTD) of selinexor in combination with FLAG-Ida regimen
时间窗: At the end of Cycle 1 (each cycle is 56 days)
A standard 3 + 3 dose escalation schedule will be used for all escalations. Initially, three patients will be entered in each cohort at the scheduled starting dose level for that cohort. If a drug-related DLT (see Section 5.1.5.3) is not seen at the scheduled dose, the dose will be escalated for the subsequent group of 3 patients. If 1 of 3 patients experiences a drug-related DLT, then 3 additional patients will receive that dose. If ≤ 2 of 6 patients experiences a drug-related DLT, the next scheduled dose level will be available. If, at a given dose level, \> 2 patients experience a drug-related DLT, the MTD will have been exceeded, additional enrollment within that cohort will cease, and dose escalation will stop. If a dose level proves intolerable (≥ 3 patients experience a DLT), enrollment will proceed at one dose-level lower.
次要结局
- Assessment of toxicity: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0(1 year)
- CR and CRi(3 months)