A Phase I Study of the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of APG-1387 as a Single Agent or in Combination With Systemic Anti-Cancer Agents in Patients With Advanced Solid Tumors or Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 90
- 试验地点
- 3
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
APG-1387 is a potent, bivalent small-molecule Inhibitor of Apoptosis Protein (IAP) antagonist. APG-1387 has shown strong dose- and schedule-dependent antitumor activities in multiple human cancer xenograft models, APG-1387 also demonstrates its synergistic effect in combination with immune checkpoint inhibitor anti-PD-1 antibody, and such a combinatory effect was further enhanced by chemotherapeutic agent. A total of 35 patients with advanced solid tumors or lymphomas have been treated with APG-1387 in two Phase I dose-escalation studies in Australia and in China. Ten dose levels have been tested ranging from 0.3 mg to 45 mg in these two studies. Based on the preliminary results, APG-1387 is well-tolerated at the dose levels evaluated to date. APG-1387 is intended for the treatment of patients with advanced solid tumors and hematologic malignancies. After establishing the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and/or recommended phase 2 dose (RP2D), several Ib /II studies will be implemented accordingly to further access the antitumor effects of APG-1387 in combination with either pembrolizumab or the chemotherapeutic agents.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed solid tumor or hematological malignancies
- •Life expectancy ≥ 3 months
- •Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
- •Corrected QT interval (QTc) ≤ 450 ms in males, and ≤ 470 ms in females
- •Adequate hematologic function
- •International normalized ratio (INR), prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤1.5 x upper limit of normal (ULN)
- •Adequate renal and liver function
- •Willingness to use contraception
- •Ability to understand and willingness to sign a written informed consent form
- •Willingness and ability to comply with study procedures and follow-up examination
- •Have provided tissue for biomarker analysis from a newly or recently-obtained biopsy of a tumor lesion not previously irradiated
排除标准
- •Received chemotherapy within 21 days (42 days for nitrosoureas or mitomycin C) prior to entering the study
- •Received hormonal, biologic (< 2 half-lives), small molecule targeted therapies or other anti-cancer therapy within 21 days of study entry
- •Radiation or surgery within 14 days of study entry, thoracic radiation within 28 days of study entry
- •Has known active central nervous (CNS) metastases and/or carcinomatous meningitis. Patients who have received prior radiotherapy for previous brain metastasis must have discontinued steroids for 14 days prior to study entry and be clinically stable
- •Continuance of toxicities due to prior radiotherapy or chemotherapy agents that do not recover to ≤ Grade 1 except alopecia
- •Requirement for corticosteroid treatment, with the exception of megestrol, local use of steroid
- •Use of therapeutic anticoagulants
- •International normalized ratio (INR) or activated partial thromboplastin time (APTT) ≥ 1.5 x ULN
- •Concurrent treatment with an investigational agent or device within 28 days prior to the first dose of therapy
- •Unstable angina, myocardial infarction, or a coronary revascularization procedure within 180 days of study entry
- •Neurologic instability per clinical evaluation due to tumor involvement of the central nervous system (CNS)
- •History of Bell's palsy
- •Active rheumatoid arthritis (RA), active inflammatory bowel disease, chronic infections, or any other disease or condition associated with chronic inflammation
- •Active infection requiring systemic antibiotic/ antifungal medication
- •Known or suspected Wilson's Disease
- •Prior treatment with IAP inhibitors
- •History of hypersensitivity to paclitaxel, or any therapeutic antibody
- •Has an active autoimmune disease, or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents
- •Is on chronic systemic steroid therapy
- •Has received a live vaccine within 30 days prior to first dose
- •Has had an allogeneic tissue/solid organ transplant, prior stem cell or bone marrow transplant
研究组 & 干预措施
APG-1387 for Injection
APG-1387 will be explored sequentially using a standard 3+3 escalation scheme at the dose escalation phase and up to 20 patient per group at the dose expansion phase.
干预措施: APG-1387 for Injection (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: 18-24 months
Patients with APG-1387 treatment related adverse events (AE), serious adverse events (SAE) will be assessed according NCI CTCAE Version 4.03
次要结局
- Pharmacokinetic evaluation(18-24 months)
- Anti-tumor effects of APG-1387 in combination with pembrolizumab or combination with paclitaxel and carboplatin in patients with advanced solid tumors(18-24 months)
- Anti-tumor effects of APG-1387 as a single agent(18-24 months)
- Preliminary biomarker assessment(18-24 months)