A Phase 1 Study of Metronomic Selinexor in Select Soft Tissue Sarcomas and Split Dosing of Selinexor in All Soft Tissue Sarcomas
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- Incidence of toxicity and safety of Selinexor given on either a metronomic (Arm A) or split dosing (Arm B) schedule: Adverse Events
研究概览
简要总结
This is a phase 1, open-label, single centre study of investigational drug selinexor in participants with soft tissue sarcomas that cannot be treated with standard therapies. Selinexor has been given to 3111 participants with cancer to date including 142 sarcoma patients. Early findings have shown that selinexor is effective in multiple cancer types. The current study is being done to test low doses and different dosing schedules of selinexor to find out if it reduces the side effects without compromising the benefits.
This study has 2 groups or Arms: Arm A and Arm B.
Arm A (Dose escalation Arm): Participants will receive selinexor by mouth 4 days a week to find out the safety, tolerability and anti-tumor effect of low doses of Selinexor in participants with advanced or metastatic malignant peripheral nerve sheath tumors (MPNST), endometrial stromal sarcomas (ESS) and leiomyosarcoma (LMS). Participants will continue on study until disease progression or unacceptable side effects. Up to 36 participants will be enrolled in this Arm.
Arm B: Participants with any soft tissue sarcoma subtypes will be enrolled in this Arm. They will receive flat doses of Selinexor by mouth once weekly, 3 times a day. Safety and tolerability will be assessed in this Arm. Up to 20 participants will be enrolled and they will continue to receive selinexor until disease progression or unacceptable side effects.
Cancer is the uncontrolled growth of human cells. One of the ways cancers cells continue to grow is by getting rid of proteins called "tumor suppressor proteins" that would normally cause cancer cells to die. The study drug works by trapping "tumor suppressor proteins" within the cell, causing the cancer cells to die or stop growing.
The study comprises 3 periods: Screening (up to 28 days), Study Drug (until disease progression), and Survival Follow-Up (once every 3 months). Procedures for research purposes only will include blood collection and study questionnaire.
详细描述
Background:
Soft tissue sarcomas (STS):
STS are a group of heterogeneous mesenchymal derived tumors with many histological types that account for approximately 1% of adult tumors and 15% of pediatric tumors. STS can be divided into those with simple genetic alterations (e.g. translocations or activating mutations) or karyotypic complex lesions. However, most subclasses are treated in the same manner. Surgery is the primary treatment for localized STS, with or without radiation therapy (RT), but approximately 10% of patients will present with metastatic disease.
For patients who present with metastatic disease, or those with locally advanced/unresectable or have failed primary therapy, cytotoxic chemotherapy is usually the treatment of choice which may provide meaningful palliation or prolong survival. Traditionally, doxorubicin containing regimens, in combination with ifosfamide or as a single agent are standard first line therapies. Combination based doxorubicin containing regimens have shown higher response rates and progression free survival at the expense of more toxicity when compared to doxorubicin alone. However, no combination regimen has been associated with increased overall survival compared to doxorubicin alone.
In the metastatic setting, STS carry a poor prognosis related to a lack of chemo-sensitivity and a lack of systemic therapeutic options. Exportin 1 (XPO1 or chromosome region maintenance 1 [CRM1]) is the sole nuclear exporter of some tumor suppressor proteins (TSP). XPO1 is over-expressed 2-4 fold in a variety of solid and hematological tumors with higher levels correlating with poorer outcomes.
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
- •Written informed consent in accordance with federal, local, and institutional guidelines
- •Age > 18 years.
- •Patients must have histologically confirmed locally advanced/unresectable or metastatic STS
- •For Arm A the acceptable histologies are MPNST, ESS and LMS
- •For Arm B arm all STS histologies are eligible
- •Patients must fall into one of the three following categories:
- •Show evidence of progressive disease on study entry; or
- •Be treatment naïve, but have progressed since diagnosis; or
- •Newly diagnosed patients with de novo metastatic measurable disease.
- •Patient must have measureable disease as defined by RECIST 1.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- •Adequate hematopoietic function within 7 days prior to C1D1:
- •absolute neutrophil count (ANC) ≥1.0x109/L
- •hemoglobin ≥ 90 g/L
- •platelet count ≥100 x 109/L
- •Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (eg, eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the Screening assessments, but they may receive growth factor support during the study.
- •Patients must have:
- •i. At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the Screening hemoglobin assessment, and
- •ii. At least a 1-week interval from the last platelet transfusion prior to the Screening platelet assessment.
- •iii. However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study.
- •Adequate hepatic function within 28 days prior to C1D1:
- •Bilirubin <1.5 times the upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of < 3 times ULN)
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2 X ULN. In the case of known (radiological and/or biopsy documented) liver metastasis, ALT/AST <5.0 X ULN is acceptable;
- •Adequate renal function within 28 days prior to C1D1: estimated creatinine clearance of ≥20 mL/min calculated using the formula of Cockcroft and Gault: (140-Age)(Weight in kg)(Constant)/(serum creatinine µmol/L); where constant is 1.23 for men and by 1.04 for women.
- •Female patients of childbearing potential must agree to use two methods of contraception (including one highly effective and one effective method of contraception) and have a negative serum pregnancy test at Screening. Male patients must use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose of study treatment.
- •Ability to swallow pills
排除标准
- •Has received selinexor or another XPO1 inhibitor previously
- •Patients who are pregnant or lactating
- •Radiation (except planned or on-going palliative radiation outside of the region of measurable disease), chemotherapy, immunotherapy, any other systemic anticancer therapy, or participation in an investigational anti-cancer study ≤3 weeks prior to initiation of therapy. Mitomycin C and radio-immunotherapy within 6 weeks prior to cycle 1 day
- •Major surgery within 4 weeks before initiation of therapy
- •Active, ongoing or uncontrolled active infection within one week prior to first dose
- •Patients with any gastrointestinal dysfunctions that could interfere with the absorption of Selinexor or patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea;
- •Inability or unwillingness to take supportive medications such as anti-nausea and anti anorexia agents as recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Antiemesis and Palliative Care.
- •In the opinion of the Investigator, patients who are significantly below their ideal body weight (Body Surface Area ≤ 1.2m2)
- •Concurrent therapy with approved or investigational anticancer therapeutic agents
- •Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study regimen or interpretation of patient safety or study results
研究组 & 干预措施
Metronomic dosing
This Arm is an open-label, non-randomized, phase 1 study of metronomic dosing of selinexor in patients with locally advanced or metastatic MPNST, ESS, LMS. Up to seven dose levels of Selinexor will be investigated.
Patients will undergo 3+3 based dose escalation to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of Selinexor.
Escalating doses of selinexor will be given starting with 2.5 mg (taken orally 4 days in a row followed by 3 days break from treatment, repeating this weekly as part of a 28-day cycle). The first dose for the first 2 patients at each dose level will be staggered by 7 days. Minimum number of patients treated in this trial arm is 18 patients, and maximum 36 patients.
Schedule:
Selinexor flat dosing with dose levels (DLs) of 2.5mg (DL1), 5mg (DL2), 7.5mg (DL3), 10mg (DL4), 12.5mg (DL5), 15mg (DL6), 17.5mg (DL7). A DL-1 (1.25 mg) is also incorporated.
干预措施: Selinexor (Drug)
Split dosing
The second arm of the study is an open-label, non randomized, phase 1b study of selinexor in patients with any histological subtype of STS administered orally one day per week, 40mg in the morning, 20mg in the afternoon and 20mg at night as part of a 28 day cycle. Twenty patients will be accrued to this arm.
干预措施: Selinexor (Drug)
结局指标
主要结局
Incidence of toxicity and safety of Selinexor given on either a metronomic (Arm A) or split dosing (Arm B) schedule: Adverse Events
时间窗: Up to 14 days after completion of study treatment
Graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Analyses will be performed using descriptive statistics.
Recommended phase 2 dose of Selinexor given metronomically
时间窗: Up to 28 days
Toxicity will be assessed using the NCI CTCAE, version 5.0. Adverse events will be tabulated and summarized by major organ category, grade, anticipation, and drug attribution.
次要结局
- Progression-Free Survival (PFS) of metronomic Selinexor(From date of first dose of selinexor until the date of first documented progression, assessed up to 12 months.)
- Objective Response Rate (ORR) of metronomic Selinexor(From date of first dose of selinexor until the date of first documented progression, assessed up to 12 months.)
- Clinical Benefit Rate (CBR) of metronomic Selinexor(From date of first dose of selinexor until the date of first documented progression, assessed up to 12 months.)
- Peak Plasma Concentration (Cmax) of metronomic Selinexor(Prior to dose on day 1, and at 1, 2, 4, and 24 hours post dose of Cycle 1, and prior to dose on Day 1 of Cycle 2 (each cycle is 28 days).)
- Area under the plasma concentration versus time curve (AUC) of metronomic Selinexor(Prior to dose on day 1, and at 1, 2, 4, and 24 hours post dose of Cycle 1, and prior to dose on Day 1 of Cycle 2 (each cycle is 28 days).)
- Characterization of the toxicity of metronomic Selinexor(Up to 14 days after completion of study treatment)
- Quality of life assessment using Quality of Life Questionnaire(Screening and then pre-dose Cycles 1, 6, and 12 (each cycle is 28 days).)