Phase I Trial of Copper Chelator in Conjunction With Pegylated Liposomal Doxorubicin and Carboplatin in Patients With Platinum-resistant/-Refractory Epithelial Ovarian Cancer, Tubal Cancer and Primary Peritoneal Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 18
- 主要终点
- Number of Participants With Dose-Limiting Toxicity (DLT)
研究概览
简要总结
Epithelial ovarian cancer (EOC) is the leading cause of gynecological malignancy-related deaths worldwide and is a substantial health threat to women. Many patients eventually develop chemoresistant relapsed disease and die despite surgery and combination chemotherapy. Progress in improving the survival in EOC has been slow, despite significant advances in treatment over the past 25 years. Tubal cancer and peritoneal cancer are thought to be similar in their origin, characteristics and treatment strategies. Based upon basic and animal studies, it is thought that copper chelators overcome platinum resistance. Thus, Trientine combined with carboplatin has been used to treat human cancers. The adverse effects (AEs) are acceptable in previously heavily-treated recurrent ovarian cancer patients, however, the treatment responses are limited. Therefore, here the investigators conduct a phase I trial of Trientine®, pegylated doxorubicin and carboplatin to find the dose-limited toxicities, and maximal toxicity dosage, and to explore whether the combination is applicable in epithelial ovarian, tubal and peritoneal cancers.
详细描述
Epithelial ovarian cancer, tubal, primary peritoneal cancers are lethal gynecologic malignances, with a 5-year survival rate below 25% for patients diagnosed with stage III-IV. Most advanced stage patients respond to cytoreductive surgery and platinum-based chemotherapy; however, >70% of women relapse, and platinum-resistant EOC is uniformly fatal. Physicians often increase the dosage of cytotoxic agents, or use single or combination second-line agents to overcome the drug resistance. Nevertheless, second-line chemotherapy sometimes may not achieve the expected cytotoxic effect and drug resistance may lead to cancer-specific death. Overcoming resistance is an important strategy for improving the therapeutic efficacy in cisplatin-containing cancer chemotherapy.
Cu homeostasis in human cells involves the inter-regulatory circuitry composed of Cu, the high-affinity Cu transporter (hCtr1) and transcription factor Sp1. Human copper transporter 1 (htr1) in humans are also involved in the import of antitumor agent cisplatin (Cp). Earlier the investigators also discovered that the magnitude of hCtr1 expression by Cu chelators depends upon the basal levels of hCtr1 expression, and that high levels of hCtr1 expression can be modulated through Cu deprivation in Cp-resistant (CpR) cells, providing a molecular basis for the development of Cu chelators as Cp resistance reversal agents in the clinical settings. D-penicillamine and Cp act synergistically to inhibit tumor growth. The investigators conduct this trial with combination agents, including LipoDox®, carboplatin and Trientine®, to develop the clinical application of copper chelator in conjunction with cytotoxic agents to conquer platinum-resistance. This trial is practical and is of perspective.
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
- 20 Years 至 75 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Histologically proved epithelial ovarian cancer, tubal cancer, and primary peritoneal cancer after surgical staging or debulking surgery
- •The first relapse within 1 year after the completion of primary platinum-based chemotherapy (partially platinum-resistant/-sensitive) or disease progression during primary chemotherapy (platinum-refractory).
- •Eastern Cooperative Oncology Group (ECOG) performance status 2 or less
- •Adequate bone marrow function (absolute neutrophil count ≥ 1,500/μl, hemoglobin ≥ 9.0 g/dL and platelet count ≥ 100,000/μl)
- •Serum creatinine ≤ 1.5 mg/dL or a calculated creatinine clearance of at least 50 mL/min, total serum bilirubin ≤ 5.0 mg/dL
- •Alanine transaminase (ALT) or aspartate aminotransferase (AST) ≤ 5 × upper normal limit
- •Patients with reproductive potential had to agree to use an effective method of birth control prior to study entry for the duration of the study participation
- •If there was no available therapy that prolonged survival for at least 3 months
排除标准
- •Patients who have metastasis to the central nervous system
- •Patients who have other malignancies within 5 years prior to study entry with the exception of carcinoma in situ of the cervix uteri and non-melanoma skin cancers
- •Patients who are receiving concurrent chemotherapy
- •Patients who have not recovered from surgery within 4 weeks of the study;
- •Patients with a clinically significant medical condition that could be aggravated by treatment or that cannot be controlled
- •Patients with medical and/or psychiatric problems of sufficient severity to limit full compliance with the study or expose patients to undue risk
- •Patients with known anaphylactic response or severe hypersensitivity to study drugs or their analogs
- •Pregnant or lactating women
- •Patients with any evidence of difficulty swallowing, intestinal obstruction or malabsorption disorder interfering with nutrition
- •Patients who were unwilling or unable to provide informed consent
研究组 & 干预措施
trientine with chemotherapy
trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1
干预措施: pegylated liposomal doxorubicin (Drug)
trientine with chemotherapy
trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1
干预措施: trientine dihydrochloride (Drug)
trientine with chemotherapy
trientine dihydrochloride PO daily (in different dose levels) plus pegylated liposomal doxorubicin IV D1 plus carboplatin IV D1
干预措施: carboplatin (Drug)
结局指标
主要结局
Number of Participants With Dose-Limiting Toxicity (DLT)
时间窗: 36 days
(1) Grade 4 neutropenia (ANC \<500/cumm\^3) or thrombocytopenia ≧7 days; (2) Hematologic toxicities ≧ Grade 3, eg. febrile neutropenia \<1,000/cumm\^3, or platelet count \<25,000/cumm\^3 with hemorrhage ≧ 7 days; (3) Non-hematologic toxicities ≧ grade 3, eg. ALT or AST, ≧ 7days; other non-hematologic toxicities ≧ grade 3 (except alopecia, non-chemotherapy related nausea/vomiting); (4) Neurologic toxicities ≧ grade 2, eg. dizziness, or lethargy ≧ 3 days
次要结局
- Overall Survival(36 months)
- Percentage of Participants With Measurable Tumor Treatment Response Assessed by RECIST Criteria 1.1(176 days)
- Maximum Tolerated Dose, MTD(within 36 days after the start of Trientine)
- Progression-free Survival(36 months)
- Maximum Plasma Concentration [Cmax] of Trientine(0, 10mins, 30mins, 60mins, 90mins, 120mins, 4h, 6h, 24h, 148h, 150h, 153h, 156h post 1st dose of trientine)
研究者
Cheng- Yang Chou
professor
National Cheng-Kung University Hospital