A Phase 1/2a, Open-Label Study of Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of SA53-OS, an MDM2 Inhibitor, in Patients With Locally Advanced or Metastatic p53 Wild-Type Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 70
- 试验地点
- 5
- 主要终点
- Phase 1: Incidence of DLT
研究概览
简要总结
The objective of this study is to assess the safety, efficacy, and pharmacokinetics of SA53-OS in adult participants with refractory solid tumors.
The study is comprised of 2 parts: Part 1 called dose escalation, and Part 2a called dose expansion. This study starts with Part 1 where participants who are diagnosed with advanced or metastatic solid tumor cancers receive different doses of SA53-OS (starting with the lowest dose) to find the maximum tolerated dose (MTD) of SA53-OS. Once the MTD of SA53-OS is known, the study continues to Part 2a where participants who are diagnosed with dedifferentiated liposarcoma (DD LPS) or other solid tumor cancers will receive SA53-OS at the MTD.
The study drug, SA53-OS, will be administered for 3 consecutive days every 3 weeks as an oral solution for up to 2 years.
详细描述
This is a phase 1/2a, open-label, dose escalation study conducted in adult participants with p53 wild-type refractory solid tumors. The study will assess the safety, efficacy, and pharmacokinetics of SA53-OS a novel MDM2 inhibitor capable of selective activation of p53. This enables the p53 tumor suppressor protein to selectively facilitate tumor cell death and growth inhibition.
The study drug, SA53-OS, will be administered for 3 consecutive days every 3 weeks as an oral solution. Phase 1 will consist of a dose escalation study to establish a candidate recommended phase 2 dose (RP2D). Phase 2a will enroll 2 expansion cohorts to establish any preliminary efficacy of SA53-OS in participants with dedifferentiated liposarcoma (DD LPS) with MDM2 amplifications and other p53 wild-type solid tumors as a single agent.
Phase 1 dose escalation:
Escalating doses of SA53-OS will be provided to participants with p53 wild-type refractory solid tumors to determine the RP2D. The MTD is the highest dose of a drug or treatment that does not cause unacceptable side effects in the first cycle. The RP2D considers all available safety, pharmacokinetics, and efficacy data including, the frequency, severity, and manageability of toxicities occurring after Cycle 1.
Phase 1 of the study will start with dose escalation by 2-fold (i.e., 2x preceding dose level) in cohorts of a single participant until Grade 2 or greater toxicity is observed.
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
- •Tumor characteristics of participants in Phase 1
- •Histologically and/or cytologically confirmed diagnosis of advanced or metastatic solid tumor and/or non-Hodgkin lymphoma excluding primary central nervous system malignancy for which no standard effective treatment exists or where that treatment was declined. Participants with non-Hodgkin lymphoma should have failed ≥ 2 prior lines of systemic therapy prior enrollment.
- •Tumor p53 wild-type.
- •Tumor characteristics of participants in Phase 2a
- •Cohort A: Tumor p53 wild-type with histologically confirmed diagnosis of advanced or metastatic DD LPS (and MDM2 amplification); OR Cohort B: Tumor p53 wild-type in other solid tumor.
- •Measurable disease by RECIST 1.
- •18 years old or older.
- •Resolution of clinically relevant toxicity-related to prior anticancer therapies prior to receipt of study treatment to Grade 1 or less.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Participants of childbearing/reproductive potential must agree to use adequate birth control measures during the course of the trial and for at least 3 months after discontinuing study treatment.
排除标准
- •Anticipated need for major surgery and/or localized palliative radiation within the next 6 weeks
- •Active, untreated central nervous system metastases. Participants with brain metastases identified at Screening may be rescreened after the lesion(s) have been appropriately treated; participants with treated brain metastases should be neurologically stable for 4 weeks post-treatment and prior to study enrollment, and off corticosteroids for at least 2 weeks before start of study treatment, and treated lesions should demonstrate no new growth on the re-screening scan.
- •Known HIV infection or active hepatitis B or C infection.
- •Thrombotic event requiring active and ongoing anticoagulation within the last 6 months prior to study treatment.
- •Myocardial infarction within the last 6 months prior to study treatment.
- •Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension or arrhythmia, congestive heart failure New York Heart Association (NYHA) Class III or IV related to primary cardiac disease, uncontrolled ischemic or severe vascular heart disease.
- •A history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
- •Known bleeding disorder (e.g., hemophilia, von Willebrand disease).
- •Conditions that may predispose to major bleeding (e.g., active GI ulcers, upper or lower GI bleedings in the last 6 months, significant hemoptysis in the last 6 months, tumor invasion of major vessels, etc.). Conditions that have been treated may be allowed if resolution of the risk is documented.
- •Use or indication for full dose anticoagulation or anti-platelet therapy including low dose aspirin.
- •Women who are pregnant or lactating.
研究组 & 干预措施
Phase 1
Dose escalation phase
干预措施: SA53-OS (phase 1) (Drug)
Phase 2
Cohort A: DDLPS (MDM2 amplified and p53 wild-type) Cohort B: other p53 wild-type solid tumors
干预措施: SA53-OS (phase 2) (Drug)
结局指标
主要结局
Phase 1: Incidence of DLT
时间窗: 21 days
Incidence of DLT in Cycle 1 (Day 1 to 21)
Phase 1 and 2: Adverse events
时间窗: Approximately 2 years
Frequency of adverse events
次要结局
- Phase 1: Peak plasma concentration(Day 4)
- Phase 2: Progression free survival (PFS)(Approximately 2 years)
- Phase 2: Overall survival(Approximately 2 years)
- Phase 2: Objective response rate (ORR)(Approximately 2 years)
- Phase 1: Area under the plasma concentration versus time curve between 0 and 24 hours(Day 4)
- Phase 2: Stable disease rate(Approximately 2 years)
- Phase 2: Disease control rate(Approximately 2 years)
- Phase 1: Half-life(Day 4)
- Phase 2: Duration of response(Approximately 2 years)
- Phase 2: Complete response rate(Approximately 2 years)