Selinexor in Combination With Methotrexate and Rituximab for Relapsed /Refractory Central Nervous System (CNS) Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 30
- 试验地点
- 5
- 主要终点
- Dose Escalation: Maximum Tolerated Dose (MTD) of Selinexor
研究概览
简要总结
This is a single-arm and open-label study to explore X+MTX+Ritu (ATG-010, Methotrexate, Rituximab) regimen in Relapse refractory PCNSL patients. Approximately 30 patients will be enrolled in the study. In dose escalation phase, patients with Relapse refractory PCNSL will be treated with X+MTX+Ritu regimen and escalating doses of oral ATG-010 weekly in a 3+3 design. Then a phase 2 expansion at the recommended dose level based on phase 1b trial will be conducted to evaluate the efficacy, safety and tolerability.
详细描述
In dose escalation phase, patients with Relapse refractory PCNSL will be treated with X+MTX+Ritu regimen （Methotrexate 3.5 g/m2, d1; Rituximab 375 mg/m2, d0）and escalating doses of oral ATG-010 weekly in a 3+3 design. ATG-010 dose level (DL) 1, 2 and 3 are 60, 80 and 100mg respectively respectively on day 1,8,15,22 for 28-days cycle.
The phase 2 expansion at the recommended dose level based on phase 1b trial. The total 6 cycles, 28 days per cycle . And, Subjects participating in the study will undergo a screening period（up to 21days）, a treatment period, and a follow-up period. The screening period is a maximum of 21 days before treatment period, And will be followed by 6 cycles of combination treatment（28 days per cycle）.
partial remission(PR) patients after induction treatment will continue ATG-010 maintenance up to 1 year or until disease progression, intolerable toxicity, death.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must meet all of the following inclusion criteria to be eligible to enroll in this study:
- •Participants must be able to understand and be willing to sign a written informed consent document.
- •Men and woman who are 18-75 years old on the day of consenting to the study.
- •Histologically documented PCNSL and SCNSL secondary to histologically documented systemic diffuse large B-cell lymphoma (DLBCL).
- •Patients must have relapsed/refractory PCNSL or relapsed/refractory SCNSL.
- •Patients must have response or remain stable disease for 2 months to prior methotrexate-based regimen.
- •Patients who had prior autologous hematopoietic stem cell transplantation are eligible.
- •Patients with parenchymal lesions must have unequivocal evidence of disease progression on imaging (MRI of the brain or head CT) 28 days prior to cycle1 day 1(C1D1). For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells.
- •Participants must have an Eastern Cooperative Oncology Group performance status of 0-
- •Participants must have adequate bone marrow and organ function shown by:
- •Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L
- •Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 14 days prior to study registration c Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days prior to study registration
- •International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal.
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal.
- •Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome.
- •Calculated creatinine clearance(CrCl)≥50ml/min using the Cockcroft-Gault equation or 24-hour urine collection.
- •Life expectancy of > 3 months.
排除标准
- •Patients with SCNSL actively receiving treatment for extra-CNS disease are excluded.
- •Lymphoma patients with only intraocular involvement.
- •Pathological diagnosis of PCNSL is T-cell lymphoma.
- •Patients with disease progression within 6 months of prior methotrexate-containing regimen.
- •patients only had received stereotactic radiation therapy as prior treatment.
- •Patients have received chemotherapy, monoclonal antibodies or targeted anticancer therapy within 21 days or 5 half-lives, whichever is shorter, prior to C1D
- •Patients with active, unstable cardiovascular diseases, fits any of the following:
- •myocardial infarction within 6 months prior to the study enrollment
- •unstable angina within 3 months prior to the study enrollment
- •Uncontrolled clinically-significant conduction abnormalities (e.g., ventricular tachycardia, ventricular fibrillation, etc.)
- •Congestive heart failure (CHF) of New York Heart Association (NYHA) ≥ Grade 3
- •Echocardiography showing left ventricular ejection fraction less than 50%
- •Uncontrolled active infection within 1 week prior to the first dose of study drug.
- •Known active hepatitis B, or C infection or HIV infection; Note: Hepatitis B virus (HBV) surface antigen (HBsAg) and or hepatitis B core antibody-positive but undetectable HBV DNA or Hepatitis C virus (HCV) antibody positive but hepatitis C virus RNA undetectable are allowed.
- •Active GI dysfunction interfering with the ability to swallow tablets, or any GI dysfunction that could interfere with absorption of study treatment.
- •Prior exposure to a selective inhibitor of nuclear export(SINE) compound, including selinexor.
- •Serious, active psychiatric, or medical conditions which, in the opinion of the Investigator, could interfere with study treatment.
研究组 & 干预措施
X-MTX-Ritu
Escalating doses of oral ATG-010 weekly in a 3+3 design. ATG-010 dose level (DL) 1, 2 and 3 are 60, 80 and 100mg respectively respectively on day 1,8,15,22 for 28-days cycle.and the phase 2 expansion at the recommended dose level based on phase 1b trial. And，
Methotrexate 3.5 g/m2, d1 and Rituximab 375 mg/m2, d0, 28-days cycle.The total 6 cycles, 28 days per cycle.
干预措施: Selinexor (Drug)
X-MTX-Ritu
Escalating doses of oral ATG-010 weekly in a 3+3 design. ATG-010 dose level (DL) 1, 2 and 3 are 60, 80 and 100mg respectively respectively on day 1,8,15,22 for 28-days cycle.and the phase 2 expansion at the recommended dose level based on phase 1b trial. And，
Methotrexate 3.5 g/m2, d1 and Rituximab 375 mg/m2, d0, 28-days cycle.The total 6 cycles, 28 days per cycle.
干预措施: Rituximab (Drug)
X-MTX-Ritu
Escalating doses of oral ATG-010 weekly in a 3+3 design. ATG-010 dose level (DL) 1, 2 and 3 are 60, 80 and 100mg respectively respectively on day 1,8,15,22 for 28-days cycle.and the phase 2 expansion at the recommended dose level based on phase 1b trial. And，
Methotrexate 3.5 g/m2, d1 and Rituximab 375 mg/m2, d0, 28-days cycle.The total 6 cycles, 28 days per cycle.
干预措施: Methotrexate (Drug)
结局指标
主要结局
Dose Escalation: Maximum Tolerated Dose (MTD) of Selinexor
时间窗: Assessed from the date of first dose of study treatment to the first cycle ends (maximum 21days)
The MTD will be determined by study definition as the highest dose level without significant safety and tolerability concern.
Dose Escalation: Recommended Phase 2 Does (RP2D) of Selinexor
时间窗: Assessed from the date of first dose of study treatment to the first cycle ends (maximum 21days)
The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for the dose expansion arms, based on safety, tolerability, efficacy data collected during the dose escalation portion of the study
Objective Response Rate (ORR)
时间窗: Cycle 1 Day 1 (each cycle consists of maximum 21 days) until a CR, CRu or PR (up to 18 cycles(each cycle is 21 days)).
ORR is defined as the proportion of patients with a best response of Complete remission (CR) or Unconfirmed(CRu), or PR during induction therapy
次要结局
- Duration of Response (DOR)(From first dose of study drug administration to end of treatment, up to 18 cycles(each cycle is 21 days))
- Overall Survival (OS)(up to 12 months)
- Progression-Free Survival (PFS)(up to 12 months)
- Number of Participants with Adverse Events(From first dose of study drug administration to end of treatment (up to 18 cycles(each cycle is 21 days)))
研究者
Tong Chen, MD
Chief physician, professor
Huashan Hospital