Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM01183 in Combination With Doxorubicin in Non-heavily Pretreated Patients With Selected Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 122
- 试验地点
- 7
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
Phase I Multicenter, Open-label, Clinical and Pharmacokinetic Study of PM01183 in Combination with Fixed Doxorubicin in Non- Heavily Pretreated Patients with Selected Advanced Solid Tumors to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of PM01183 in combination with doxorubicin, to characterize the safety profile and feasibility of this combination, to characterize the pharmacokinetics (PK) of this combination, to obtain preliminary information on the clinical antitumor activity,to explore the feasibility, safety and efficacy of a potential improvable dose of this combination in selected tumor types [i.e. small cell lung cancer (SCLC) and endometrial cáncer] and to evaluate the pharmacogenomics (PGx) in tumor samples of patients exposed to PM01183 and doxorubicin at the RD in order to assess potential markers of response and/or resistance.
详细描述
The study has currently met its primary end point and is now recruiting patients to be treated at the RD expansion cohort of selected tumor types, specifically: endometrial adenocarcinomas, neuroendocrine tumors, and small-cell lung cancer (SCLC).
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
- •Voluntarily written informed consent
- •Age: between 18 and 75 years (both inclusive).
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤
- •Cohort of patients with SCLC and endometrial cáncer ECOG PS ≤
- •Life expectancy ≥ 3 months.
- •Patients with a histologically/cytologically confirmed diagnosis of advanced disease of any of the following tumors:
- •Breast cancer
- •Soft-tissue sarcoma
- •Primary bone sarcomas.
- •Gynecologic tumors (endometrial adenocarcinomas, epithelial ovarian cancer...)
- •Hepatocellular carcinoma
- •Gastroenteropancreatic neuroendocrine tumors
- •Small cell lung cancer (SCLC)
- •Gastric cancer
- •Bladder cancer
- •Adenocarcinoma of unknown primary site
- •At least three weeks since the last anticancer therapy, including radiotherapy
- •Adequate bone marrow, renal, hepatic, and metabolic function
- •Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within normal range (according to institutional standards).
- •Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six weeks after discontinuation of treatment
排除标准
- •Concomitant diseases/conditions:
- •History or presence of unstable angina, myocardial infarction, congestive heart failure, or clinically significant valvular heart disease within last year.
- •Symptomatic or any uncontrolled arrhythmia
- •Ongoing chronic alcohol consumption, or cirrhosis
- •Active uncontrolled infection.
- •Known human immunodeficiency virus (HIV) infection.
- •Any other major illness that, in the Investigator's judgment
- •Brain metastases or leptomeningeal disease involvement.
- •Men or women of childbearing potential who are not using an effective method of contraception
- •Patients who have had radiation therapy in more than 35% of the bone marrow. This criterion will not apply to cohort of patients with SCLC and endometrial cáncer.
- •History of previous bone marrow and/or stem cell transplantation.
研究组 & 干预措施
lurbinectedin (PM01183) / doxorubicin
干预措施: lurbinectedin (PM01183) (Drug)
lurbinectedin (PM01183) / doxorubicin
干预措施: Doxorubicin (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: During the first cycle of treatment, up to 28 days
A minimum of three patients will be included at each DL. If no patients experience a DLT during Cycle 1, the dose will be escalated. If one of three patients experiences a DLT, three additional patients will be included at that level. If \>1 evaluable patient during dose escalation at a given DL experience a DLT during Cycle 1, that DL will be considered the MTD and dose escalation will be terminated, except if all DLTs are related to neutropenia exclusively, in which case dose escalation may be resumed as originally planned in a new cohort of patients but with compulsory primary G-CSF prophylaxis.
Recommended Dose (RD)
时间窗: During the first cycle of treatment, up to 28 days
The DL immediately below the MTD, or DL4 if the MTD is not yet defined during dose escalation before the last DL (i.e., DL4) is reached, was to be initially expanded up to a minimum of nine evaluable patients. If less than three among the first nine evaluable patients treated within the expansion cohort experience a DLT during Cycle 1, this DL will be the RD.
Number of Participants With Dose-limiting Toxicities
时间窗: During the first cycle of treatment, up to 28 days
DLT,dose-limiting toxicity Patients enrolled into this study were originally not allowed to receive primary G-CSF prophylaxis. However, the finding of dose-limiting febrile neutropenia in two patients treated at dose level I in the present study (see below) suggested that increasing doses of the DOX/PM01183 combination might require primary G-CSF prophylaxis to decrease the risk of febrile neutropenia. Therefore, a separate dose escalation was established to define the MTD and the RD of the DOX/PM01183 combination with compulsory primary G-CSF prophylaxis.
次要结局
- Progression-free Survival(Time from the date of first administration to the date of PD or death (of any cause), whichever came first, assessed up to 72 months)
- Duration of Response(Time from the time measurement criteria are met for complete response, whichever is first recorded, until the first date in which progressive disease is objectively documented or the date of death, assessed up to 72 months)
- Overall Survival(Time from the date of first administration to the date of death (of any cause), assessed up to 72 months)
- Best Overall Tumor Response(Tumor assessments were done every six weeks up to study completion)