Phase 1 Study of Selinexor in Combination With Topoisomerase-II Inhibition in Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- MTD of selinexor, defined as the highest safely tolerated dose where, at most, one patient experiences DLT in 6 evaluable patients, with the next higher dose having at least 2 patients who experience DLT
研究概览
简要总结
This phase I trial studies the side effects and best dose of selinexor when given together with etoposide with or without mitoxantrone hydrochloride and cytarabine in treating patients with acute myeloid leukemia that has returned (relapsed) or has not responded to treatment (refractory). Selinexor may help stop the growth of tumor cells by blocking an enzyme needed for cancer cell growth. Drugs used in chemotherapy, such as etoposide, mitoxantrone hydrochloride, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy together with selinexor work better in treating relapsed or refractory acute myeloid leukemia.
详细描述
PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of selinexor in combination with mitoxantrone hydrochloride, etoposide, cytarabine (MEC) or oral etoposide (respective cohorts are independent of each other) in patients with relapsed or refractory acute myeloid leukemia (AML).
II. To define the specific toxicities, maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of these combinations.
III. To determine the recommended phase 2 dose (RP2D) of these combinations.
SECONDARY OBJECTIVES:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Patients with relapsed or refractory AML; Cohort A patients must be < 60 years of age and have failed at least one prior induction regimen for AML; Cohort B patients must be ≥ 60 years of age, unfit for intensive therapy (physician opinion), and have failed an induction regimen for AML. The maximum number of prior lines of induction for both cohorts is 3
- •Patients with secondary AML or therapy related disease (t-AML) are eligible
- •If the patient has co-morbid medical illness, life expectancy attributed to this must be greater than 6 months
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- •Total bilirubin < 2.0 mg/dL, except when patient is known to have Gilbert's Syndrome, the total bilirubin can be ≤3.0 mg/dL.
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X institutional upper limit of normal
- •Creatinine (Cr) clearance > 50 mL/min by Modification of Diet in Renal Disease (MDRD) calculation
- •New York Heart Association (NYHA) congestive heart failure (CHF) class II or better
- •Cardiac ejection fraction >= 50%
- •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 the written informed consent document
排除标准
- •Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
- •Patients receiving any other investigational agents or patients that have received other investigational agents within 14 days of enrollment
- •Patients with active central nervous system (CNS) malignancy; asymptomatic small lesions are not considered active; treated lesions may be considered inactive if they are stable for at least 3 months; patients with malignant cells in their cerebrospinal fluid (CSF) without CNS symptoms may be included
- •Major surgery within 2 weeks before day 1
- •Uncontrolled active infection; patients with infection requiring parenteral antibiotics are eligible if the infection is controlled
- •Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea
- •History of seizures, movement disorders or cerebrovascular accident within the past 3 years prior to cycle 1 day 1
- •Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased visual acuity
- •Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association [NYHA) class III or IV), unstable angina pectoris, myocardial infarction within 6 months prior to enrollment, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
- •Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study
- •Pregnant women or women who are breastfeeding are excluded from this study; confirmation that the subject is not pregnant must be established by a negative serum beta (β)-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women
- •Patients with advanced malignant solid tumors
- •Patients whom, in the opinion of the investigators, are significantly below their ideal body weight
- •Patients who are not able to swallow capsules or tablets
研究组 & 干预措施
Cohort A (mitoxantrone, etoposide, cytarabine, selinexor)
Patients receive mitoxantrone hydrochloride IV, etoposide IV, and cytarabine IV QD on days 1-6 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment continues for 1 course (28 days). Further treatment is based on disease response. Patients achieving CR/CRi are evaluated for stem cell transplant; patients who do not proceed to transplant may receive selinexor as monotherapy in the absence of disease progression or unacceptable toxicity.
干预措施: mitoxantrone hydrochloride (Drug)
Cohort A (mitoxantrone, etoposide, cytarabine, selinexor)
Patients receive mitoxantrone hydrochloride IV, etoposide IV, and cytarabine IV QD on days 1-6 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment continues for 1 course (28 days). Further treatment is based on disease response. Patients achieving CR/CRi are evaluated for stem cell transplant; patients who do not proceed to transplant may receive selinexor as monotherapy in the absence of disease progression or unacceptable toxicity.
干预措施: etoposide (Drug)
Cohort A (mitoxantrone, etoposide, cytarabine, selinexor)
Patients receive mitoxantrone hydrochloride IV, etoposide IV, and cytarabine IV QD on days 1-6 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment continues for 1 course (28 days). Further treatment is based on disease response. Patients achieving CR/CRi are evaluated for stem cell transplant; patients who do not proceed to transplant may receive selinexor as monotherapy in the absence of disease progression or unacceptable toxicity.
干预措施: cytarabine (Drug)
Cohort A (mitoxantrone, etoposide, cytarabine, selinexor)
Patients receive mitoxantrone hydrochloride IV, etoposide IV, and cytarabine IV QD on days 1-6 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment continues for 1 course (28 days). Further treatment is based on disease response. Patients achieving CR/CRi are evaluated for stem cell transplant; patients who do not proceed to transplant may receive selinexor as monotherapy in the absence of disease progression or unacceptable toxicity.
干预措施: selinexor (Drug)
Cohort A (mitoxantrone, etoposide, cytarabine, selinexor)
Patients receive mitoxantrone hydrochloride IV, etoposide IV, and cytarabine IV QD on days 1-6 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment continues for 1 course (28 days). Further treatment is based on disease response. Patients achieving CR/CRi are evaluated for stem cell transplant; patients who do not proceed to transplant may receive selinexor as monotherapy in the absence of disease progression or unacceptable toxicity.
干预措施: laboratory biomarker analysis (Other)
Cohort A (mitoxantrone, etoposide, cytarabine, selinexor)
Patients receive mitoxantrone hydrochloride IV, etoposide IV, and cytarabine IV QD on days 1-6 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment continues for 1 course (28 days). Further treatment is based on disease response. Patients achieving CR/CRi are evaluated for stem cell transplant; patients who do not proceed to transplant may receive selinexor as monotherapy in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological study (Other)
Cohort B (etoposide, selinexor)
Patients receive etoposide PO QD on days 1-5 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment may repeat every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving response after 4 courses discontinue treatment; patients achieving response may receive up to 4 courses of maintenance therapy every 8 weeks. Patients may then continue selinexor as monotherapy at the discretion of the principal investigator.
干预措施: etoposide (Drug)
Cohort B (etoposide, selinexor)
Patients receive etoposide PO QD on days 1-5 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment may repeat every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving response after 4 courses discontinue treatment; patients achieving response may receive up to 4 courses of maintenance therapy every 8 weeks. Patients may then continue selinexor as monotherapy at the discretion of the principal investigator.
干预措施: selinexor (Drug)
Cohort B (etoposide, selinexor)
Patients receive etoposide PO QD on days 1-5 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment may repeat every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving response after 4 courses discontinue treatment; patients achieving response may receive up to 4 courses of maintenance therapy every 8 weeks. Patients may then continue selinexor as monotherapy at the discretion of the principal investigator.
干预措施: laboratory biomarker analysis (Other)
Cohort B (etoposide, selinexor)
Patients receive etoposide PO QD on days 1-5 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment may repeat every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving response after 4 courses discontinue treatment; patients achieving response may receive up to 4 courses of maintenance therapy every 8 weeks. Patients may then continue selinexor as monotherapy at the discretion of the principal investigator.
干预措施: pharmacological study (Other)
结局指标
主要结局
MTD of selinexor, defined as the highest safely tolerated dose where, at most, one patient experiences DLT in 6 evaluable patients, with the next higher dose having at least 2 patients who experience DLT
时间窗: 28 days
The National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 will be used to characterize toxicities.
次要结局
- Duration of response(Up to 30 days after completion of study treatment)
- Degree of response(Up to 30 days after completion of study treatment)
- ORR(Up to 30 days after completion of study treatment)
研究者
Alice Mims
Principal Investigator
Ohio State University Comprehensive Cancer Center