A Phase 2 Open-Label Multicenter Study to Evaluate the Safety and Efficacy of Selinexor With or Without Pembrolizumab Versus Standard of Care in Previously Treated Metastatic Colorectal Cancer With RAS Mutations
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 13
- 试验地点
- 3
- 主要终点
- Arm B and C: Progression-free Survival (PFS) as Assessed by the Investigator Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
研究概览
简要总结
The purpose of this study is to evaluate the efficacy and safety of selinexor alone or with pembrolizumab in participants with advanced or metastatic colorectal cancer (CRC). Approximately 78 participants with advanced or metastatic CRC will be enrolled, and randomized (1:1:1) into three arms A (selinexor only), B (selinexor and pembrolizumab), and C (standard of care [Combination of trifluridine and tipiracil]). Randomization will be based on stratification factors: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 versus 2. The end of treatment (EoT) visit will occur less than or equal to (<=30) days post-treatment discontinuation. A survival follow-up visit will be performed every 3 months from EoT and will continue for 12 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- •Participants have histologically proven diagnosis of unresectable metastatic colorectal cancer with a known rat sarcoma (RAS) mutation.
- •Participants have measurable disease according to RECIST 1.1 criteria.
- •Have received 2-3 prior lines of systemic anticancer treatment (adjuvant or neoadjuvant therapy is not counted as one line of systemic therapy).
- •Participants with stable previously treated brain metastases are allowed.
- •ECOG performance status of 0-2 at the time of screening.
- •Age ≥ 18 years at the time of signing informed consent
- •Life expectancy of at least 3 months.
- •Female participants of childbearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male participants must use an effective barrier method of contraception if sexually active throughout the study and for 4 months after the last dose of selinexor or pembrolizumab or 6 months after trifluridine and tipiracil.
- •Written informed consent signed in accordance with federal, local, and institutional guidelines.
排除标准
- •Prior treatment with a selective inhibitor of nuclear export (SINE) compound or selinexor.
- •Prior treatment with immune checkpoint inhibitors.
- •Participants with microsatellite instability high (MSI-H) or deficient mismatch repair (dMMR).
- •Known allergy to any of study drugs (selinexor, pembrolizumab, and trifluridine and tipiracil) or the excipient of pembrolizumab.
- •Significant cardiovascular impairment, defined as:
- •Left ventricular ejection fraction ≤ 40 percent (%)
- •Active congestive heart failure (New York Heart Association [NYHA]) Class ≥ 3
- •Unstable angina or myocardial infarction within 3 months of enrollment
- •Serious and potentially life-threatening arrhythmia
- •Impaired hematopoietic function (any of the following would result in exclusion):
- •Absolute neutrophil count (ANC) less than (<) 1500/cubic millimeter (mm^3)
- •Platelet count < 100,000/ mm^3
- •Hemoglobin (Hb) < 10 gram per deciliter (g/dL)
- •Significant renal impairment, defined as: calculated creatinine clearance (CrCl) of < 30 milliliter per minute (mL/min) using the formula of Cockcroft and Gault.
- •Impaired hepatic function defined as: total bilirubin greater than (>) 1.5 × upper limit of normal (ULN) and aspartate transaminase (AST) > 2.5 x ULN, AST > 2.5 x ULN; for Arm B, unless bilirubin elevation is related to Gilbert's Syndrome for which bilirubin must be ≤ 4 x ULN.
- •Participants with a diagnosis of immunodeficiency or are receiving systemic steroid therapy (>10 mg/day of prednisone or equivalent) or any other form of immunosuppressive therapy. Participants with active autoimmune disease requiring systemic treatment during the past 2 years.
- •Participants with controlled type I and type II diabetes mellitus, and endocrinopathies such as hypothyroidism on stable hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are allowed.
- •Note: The Investigator needs to evaluate the participants medical history to confirm that they are eligible to receive the combination with pembrolizumab per these criteria.
- •Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as:
- •Not recovered from major surgery ≤ 21 days prior to Day 1 dosing. Minor procedures, such as biopsies, dental work, or placement of a port or IV line for infusion are permitted.
- •Have ongoing clinically significant anti-cancer therapy-related toxicities Common Terminology Criteria for Adverse Events (CTCAE) Grade >
- •In specific cases, participants whose toxicity has stabilized or with Grade 2 non-hematologic toxicities can be allowed following documented approval by the Sponsor's Medical Monitor.
- •Had last dose of previous anti-cancer therapy ≤14 days prior to Day 1 dosing.
- •Palliative radiotherapy > 14 days prior to the study is allowed.
- •Received investigational drugs in other clinical trials within 28 days, or 5 half-lives of the investigational drug (whichever is shorter), prior to Cycle 1 Day 1 (C1D1).
- •Live-attenuated vaccine against an infectious disease (e.g., nasal spray influenza vaccine) ≤ 14 days prior to the intended C1D
- •Female participants who are pregnant or lactating.
- •Active, ongoing or uncontrolled active infection requiring parenteral antibiotics, antivirals, antifungals within 1 week of Screening.
- •Participants with autoimmune disease, a medical condition that requires systemic corticosteroids or other immunosuppressive medication; or a history of interstitial lung disease.
- •Any gastrointestinal dysfunctions that could interfere with the absorption of selinexor (e.g. bowel obstruction, inability to swallow tablets, malabsorption syndrome, unresolved nausea, vomiting, diarrhea CTCAE > grade 1).
- •In the opinion of the investigator, participants who are below their ideal body weight and would be unduly impacted by changes in their weight.
- •Serious psychiatric or medical conditions that could interfere with participation in the study or in the opinion of the Investigator would make study involvement unreasonably hazardous.
- •Concurrent therapy with approved or investigational anticancer therapeutic including topical therapies.
研究组 & 干预措施
Arm A: Selinexor 80 mg
Participants received a single dose of selinexor 80 mg (4 tablets of 20 mg) orally QW on Day 1 of each week of a 42-day cycle (i.e., on Days 1, 8, 15, 22, 29, and 36 of each 42-day cycle) until PD, intolerable toxicity, or withdrawal from the study (maximum exposure: 33 weeks).
干预措施: Selinexor (Drug)
Arm B: Selinexor 80 mg and Pembrolizumab 400 mg
Participants received a single dose of selinexor 80 mg (4 tablets of 20 mg) orally QW on Day 1 of each week of a 42-day cycle (i.e., on Days 1, 8, 15, 22, 29, and 36 of each 42-day cycle) in combination with pembrolizumab 400 mg IV once every 6 weeks of each 42-day cycle until PD, intolerable toxicity, or withdrawal from the study (maximum exposure: 30 weeks).
干预措施: Selinexor (Drug)
Arm B: Selinexor 80 mg and Pembrolizumab 400 mg
Participants received a single dose of selinexor 80 mg (4 tablets of 20 mg) orally QW on Day 1 of each week of a 42-day cycle (i.e., on Days 1, 8, 15, 22, 29, and 36 of each 42-day cycle) in combination with pembrolizumab 400 mg IV once every 6 weeks of each 42-day cycle until PD, intolerable toxicity, or withdrawal from the study (maximum exposure: 30 weeks).
干预措施: Pembrolizumab (Drug)
Arm C: Standard of care (SOC)
Participants received combination of trifluridine and tipiracil 35 mg/m^2/dose tablets orally BID (maximum 80 mg per dose) as SOC on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until PD, intolerable toxicity, or withdrawal from the study (maximum exposure: 11 weeks).
干预措施: Trifluridine (Drug)
Arm C: Standard of care (SOC)
Participants received combination of trifluridine and tipiracil 35 mg/m^2/dose tablets orally BID (maximum 80 mg per dose) as SOC on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until PD, intolerable toxicity, or withdrawal from the study (maximum exposure: 11 weeks).
干预措施: Tipiracil (Drug)
结局指标
主要结局
Arm B and C: Progression-free Survival (PFS) as Assessed by the Investigator Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
时间窗: From the date of randomization until disease progression or death, whichever occurs first (up to 8 months)
PFS was defined as the time from the date of randomization until disease progression or death due to any cause, whichever occurs first. PFS was assessed by the investigator per RECIST 1.1. As per RECIST 1.1 criteria, PD was defined as at least a 20% increase in the sum of the longest diameter (SLD), taking as reference the smallest sum of the longest diameter (SLD) recorded from baseline or the appearance of 1 or more new lesions.
次要结局
- Arm B and C: Duration of Response (DOR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1(From first occurrence of CR or PR until disease progression or death, whichever occurs first (up to 8 months))
- Arm A and C: Duration of Response (DOR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1(From first occurrence of CR or PR until disease progression or death, whichever occurs first (up to 8 months))
- Arm A, B and C: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs(From start of study drug administration up to 12 months)
- Arm A and C: Overall Response Rate (ORR)(From the date of randomization until the documentation of CR or PR, whichever occurs first (up to 8 months))
- Arm A, B and C: Progression-free Survival (PFS) at 6 Months(At 6 Months)
- Arm B and C: Percentage of Participants With Confirmed Disease Control Rate as Per Response Evaluation Criteria in Solid Tumors Version 1.1(From the date of randomization up to death (up to 8 months))
- Arm A and C: Percentage of Participants With Confirmed Disease Control Rate as Per Response Evaluation Criteria in Solid Tumors Version 1.1(From the date of randomization up to death (up to 8 months))
- Arm A, B and C: Overall Survival (OS)(From the date of randomization up to death (up to 8 months))
- Arm B and C: Overall Response Rate (ORR)(From the date of randomization until the documentation of CR or PR, whichever occurs first (up to 8 months))
- Arm A, B and C: Percentage of Participants With Overall Survival (OS) at 6 Months(At 6 Months)
- Arm A, B and C: Percentage of Participants With Overall Survival (OS) at 12 Months(At 12 Months)