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临床试验/NCT02416908
NCT02416908已完成1 期

An Investigator Sponsored Phase I/II Study of CLAG + Selinexor in Relapsed or Refractory Acute Myeloid Leukemia

Washington University School of Medicine1 个研究点 分布在 1 个国家目标入组 40 人开始时间: 2015年6月16日最近更新:
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适应症
干预措施
相关药物

试验速览

阶段
1 期
状态
已完成
入组人数
40
试验地点
1
主要终点
Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants
研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

Selinexor has shown single-agent activity in a current phase I study enrolling patients with relapsed/refractory AML with durable complete remissions (CR), complete remissions with incomplete hematologic recovery (CRi), partial remissions (PR), and stable disease (SD) observed. Furthermore, common toxicities included nausea, fatigue, and anorexia and were manageable with supportive care agents. Additionally, CLAG chemotherapy has proven activity in relapsed and refractory AML, and has been shown to be a relatively well tolerated regimen without significant non-hematologic toxicity. Given the established role of CLAG chemotherapy, the single agent activity of selinexor, and their non-overlapping toxicities, the investigators propose a phase I/II open label study of selinexor in combination with CLAG for the treatment of patients with relapsed/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
None

入排标准

年龄范围
18 Years 至 70 Years（Adult, Older Adult）
性别
All
接受健康志愿者
否

入选标准

  • •Histologically confirmed AML (defined using WHO criteria) with one of the following:
  • •Primary refractory disease following ≤ 2 cycles of induction chemotherapy, or
  • •First relapse with no prior unsuccessful salvage chemotherapy, or
  • •Relapsed or refractory to hypomethylating agent, defined as a lack of response, disease progression, loss of response, or intolerance as deemed by the study investigator
  • •Age between 18 and 70 years old.
  • •ECOG performance status ≤ 3
  • •Adequate organ function as defined below:
  • •AST(SGOT), ALT(SGPT), total bilirubin ≤ 2 x IULN except when in the opinion of treating physician is due to direct involvement of leukemia (eg. hepatic infiltration or biliary obstruction due to leukemia) or Gilbert's disease
  • •Creatinine clearance >50 ml/min, calculated using the formula of Cockroft and Gault: (140-Age) x Mass (kg) / (72 x Creatinine mg/dL); multiply by 0.85 if female.
  • •Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram
  • •To ensure that no patient will receive a dose of selinexor >70mg/m^2, body surface area (BSA) calculated by Dubois method must be >1.43 m^2
  • •Patients should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. Women should not breastfeed a baby while on this study. It is important patients understand the need to use birth control while on this study. It is not anticipated that female patients enrolling in this study will be able to conceive. However, in the rare event that this is possible, female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose.
  • •Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

排除标准

  • •Acute promyelocytic leukemia (AML with t(15;17)(q22;q11) and variants).
  • •Previous treatment with CLAG or other chemotherapy regimen containing both cladribine and cytarabine.
  • •Colony stimulating factors within 2 weeks of study.
  • •Active graft versus host disease (GVHD) after allogeneic stem cell transplantation. At least 2 months must have elapsed since completion of an allogeneic stem cell transplantation.
  • •Less than 2 weeks from the completion of any previous cytotoxic chemotherapy (with the exception of hydroxyurea).
  • •Concurrent active malignancy under treatment except prostate or breast cancer undergoing treatment with hormonal therapy.
  • •Treatment with any investigational agent within three weeks prior to first dose in this study.
  • •Active CNS involvement with leukemia.
  • •Unstable cardiovascular function:
  • •symptomatic ischemia, or
  • •uncontrolled clinically significant conduction abnormalities (i.e. ventricular tachycardia on antiarrhythmics are excluded and 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
  • •A history of allergic reactions attributed to compounds of similar chemical or biologic composition to KPT-330 or other agents used in the study.
  • •Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines is acceptable.
  • •Any medical condition which, in the investigator's opinion, could compromise the patient's safety.
  • •Pregnant and/or breastfeeding. Patient must have a negative urine pregnancy test within 5 days of study entry.
  • •Unable to swallow tablets, or diagnosed malabsorption syndrome, or any other disease significantly affecting gastrointestinal function.
  • •Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen).
  • •Known human immunodeficiency virus (HIV) infection.
  • •Serious psychiatric or medical conditions that could interfere with treatment.

研究组 & 干预措施

Phase I Schedule A (selinexor)

Experimental
  • Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Cladribine (Drug)

Phase I Schedule A (selinexor)

Experimental
  • Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Selinexor (Drug)

Phase I Schedule A (selinexor)

Experimental
  • Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: G-CSF (Drug)

Phase I Schedule A (selinexor)

Experimental
  • Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Cytarabine (Drug)

Phase I Schedule A (selinexor)

Experimental
  • Selinexor will be dosed on Days 1, 5, 10, and 12 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Bone marrow biopsy (Procedure)

Phase I Schedule B (selinexor)

Experimental
  • Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Selinexor (Drug)

Phase I Schedule B (selinexor)

Experimental
  • Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Cladribine (Drug)

Phase I Schedule B (selinexor)

Experimental
  • Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: G-CSF (Drug)

Phase I Schedule B (selinexor)

Experimental
  • Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Cytarabine (Drug)

Phase I Schedule B (selinexor)

Experimental
  • Selinexor will be dosed on Days 1, 5, 10, 12, 17, and 19 of the 28-day cycle. All doses will be 60 mg each PO.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Bone marrow biopsy (Procedure)

Phase II (selinexor)

Experimental
  • Selinexor will be given at the schedule as determined in Phase 1.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Selinexor (Drug)

Phase II (selinexor)

Experimental
  • Selinexor will be given at the schedule as determined in Phase 1.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Cladribine (Drug)

Phase II (selinexor)

Experimental
  • Selinexor will be given at the schedule as determined in Phase 1.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: G-CSF (Drug)

Phase II (selinexor)

Experimental
  • Selinexor will be given at the schedule as determined in Phase 1.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Cytarabine (Drug)

Phase II (selinexor)

Experimental
  • Selinexor will be given at the schedule as determined in Phase 1.
  • Single agent selinexor maintenance may be given at 60 mg on Days 1, 8, 15, and 22 (4 doses per 28 day cycle).
  • Cladribine will be given 5 mg/m^2/day IV once daily on Days 4-8.
  • G-CSF will be given 300 mcg SC once daily on Days 3-8.
  • Cytarabine will be given 2000 mg/m^2/day IV once daily on Days 4-8.
  • Bone marrow biopsy will be performed at baseline, Day 3, at time of hematopoietic recovery, and as clinically indicated to assess treatment response.

干预措施: Bone marrow biopsy (Procedure)

结局指标

主要结局

Safety and Tolerability of Treatment as Measured by Incidence of Grade 3-4 Adverse Events Occurring in >5% of Participants

时间窗: From start of treatment until 30 days following last day of study treatment or until the start of a subsequent treatment for AML, whichever came first (41 days)

-All adverse events will be classified using the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0

Complete Remission Rate (CR + CRi)

时间窗: Median follow-up of 34 days

* Morphologic complete remission (CR): neutrophil count \> 1.0 x 109 /L, platelet count ≥ 100 x 109/L, \< 5% bone marrow blasts by morphologic review, no Auer rods, no evidence of extramedullary disease. (No requirements for marrow cellularity, hemoglobin concentration). * Morphologic complete remission with incomplete blood count recovery (CRi): same as CR but ANC may be \<1000/mcl or platelet count \<100,000/mcl * Participants in the phase I portion of the study, treated at the MTD will count towards the phase II accrual goal for evaluation of the primary endpoint.

次要结局

  • Time to Platelet Engraftment(56 days)
  • Overall Survival(Up to 2 years (median follow-up of 307 days))
  • Time to Neutrophil Engraftment(Up to 2 years)
  • Number of Participants Who Were Able to Undergo Hematopoietic Stem Cell Transplantation(Up to 2 years (median follow-up of 307 days))
  • Duration of Remission(Up to 2 years)
  • Event-free Survival(Up to 2 years (median follow-up of 307 days))
  • Relapse-free Survival(Median follow-up of 307 days)

研究者

申办方类型
Other
责任方
Sponsor

研究点 (1)

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