Multicenter, Prospective, Non-randomized, Phase II Trial Designed to Evaluate the Activity of Cabazitaxel in Patients With Advanced Adreno-Cortical- Carcinoma Progressing After Previous Chemotherapy Lines
试验速览
- 阶段
- 2 期
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- To assess the clinical benefit after 4 months of the cabazitaxel in patients with locally advanced or metastatic ACC who progressed after cytotoxic therapy.
研究概览
简要总结
Adrenocortical cancer (ACC) is a rare aggressive tumor. The treatment of metastatic ACC is challenging and the current available treatments are mitotane, chemotherapy or the combination of both. Prognosis in locally advanced inoperable and metastatic ACC patients still remains poor, the 5-year overall survival being <15%. New treatment strategies are therefore needed. The taxanes are a class of drugs targeting the microtubules that have shown to be effective in the treatment of several malignancies but have not been fully developed in patients with ACC. Cabazitaxel is a new taxoid which promotes the tubulin assembly in vitro and stabilizes microtubules against cold-induced depolymerization as efficiently as docetaxel. Cabazitaxel was selected for development based on a better antiproliferative activity on resistant cell lines than docetaxel. The activity of the drug against several malignancies is currently tested in ongoing prospective studies, but to our knowledge neither preclinical nor clinical studies are currently testing cabaztaxel in ACC. This study is aimed to demonstrate that cabazitaxel is active in ACC, but the drug was never tested before in this clinical setting. A prospective, non-randomized, multicentre, open label, single arm, phase II study will be conducted in patients with advanced ACC. The phase II study will be conducted in 2 different Italian Institutions that are reference centers for ACC.
详细描述
CABAZITAXEL ADMINISTRATION Cabazitaxel will be administered at dose of 25 mg/m2 every 3 weeks, administered by IV route in 1 hour, for a maximum of 6 total cycles. The drug will be provided by Sanofi -Aventis S.p.A. Concomitant mitotane therapy will not be permitted however mitotane will be maintained in patients with hormone secreting tumors. Cycle length for cabazitaxel is 3 weeks. New cycles of therapy may not begin until Absolute Neutrophil Count (ANC) ≥1500/mm3, platelet count ≥75 000/mm3, and non-hematological toxicities (except alopecia) have recovered to baseline.
A maximum of 2 weeks delay is allowed between 2 treatment cycles.
PHARMACOKINETIC STUDY Another study aims will be to assess the toxicity of cabazitaxel therapy in ACC patients. As mitotane notoriously interfere with the metabolism of several drugs (11), an ancillary study will be conducted to assess the pharmacokinetic profile of cabazitaxel in the patient population with hormone secreting tumors that will maintain mitotane administration vs patients with non secreting ACC in which mitotane will be stopped. Blood samples will be collected in lithium heparinized tubes at fixed time points before and after drug infusion: Cycles 1 on Day 1 just before infusion, 30 min after start of infusion, 5 min before the end of 1-hour infusion (Tmax), 24 h, 48h and 96 h post-infusion. Cabazitaxel serum concentrations will be measured in plasma using a validated liquid chromatography-tandem mass spectrometry method: the Agilent 1260 Infinity LC equipped with an Agilent 6460 Triple Quadrupole Mass Spectrometer (QQQ) in electrospray mode systems.
STATISTICAL ANALYSIS All data collected at baseline, including recorded and derived variables will be described on all patients by means of summary descriptive statistics: mean, standard deviation, median, min, max, 25th and 75th percentiles for continuous variables; absolute and relative frequency for categorical variables. The relative frequencies will be calculated on the total patients with and without missing data. Whenever possible the data will be described by visit.
Chi square ore Fisher test, when applicable will be employed to compare categorical variables. Student T-test and analysis of variance for parametric or Wilcoxon's matched pairs signed-rank test and Friedman analysis of variance for non parametric data will be used to compare paired data. Simple correlation analysis will be performed by Spearman rho (coefficient of Spearman's rank correlation) for nonparametric distribution. Two-tailed tests will be used for all comparisons and p <0.05. All survival functions will computed using the Kaplan-Meier method. Survival curves will be compared with the log rank test.
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 confirmed diagnosis of ACC
- •Locally advanced or metastatic disease not amenable to radical surgery resection
- •Radiologically monitorised disease
- •Progressing disease after one to three cytotoxic chemotherapy regimes (including a platin-based protocol)
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Life expectancy ≥ 3 months
- •Age ≥ 18 years
- •Adequate bone marrow reserve (neutrophils ≥ 1500/mm³ and platelets > 100.000/mm³)
- •Effective contraception in pre-menopausal female and male patients
- •Patient´s written informed consent
- •Ability to comply with the protocol procedures
- •Mitotane intake should be stopped one months before the study entry
排除标准
- •History of prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, or other treated malignancies with no evidence of disease for at least three years.
- •Serum creatinine > 1.5 x ULN or hepatic insufficiency, Hemoglobin <10.0 g/dL;
- •Total bilirubin >1x ULN, Creatinine < 1.5 ULN;
- •Decompensated heart failure (ejection fraction <45%), myocardial infarction or revascularization procedure during the last 6 months, unstable angina pectoris, uncontrolled cardiac arrhythmia
- •Pregnancy or breast feeding
- •Any other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study
- •Patients with serum levels of mitotane (evaluated one week before the study start) in the therapeutic range (14-20 mcg/ml).History of severe hypersensitivity reaction (≥grade 3) to docetaxel
- •History of severe hypersensitivity reaction (≥grade 3) to polysorbate 80 containing drugs
- •Uncontrolled severe illness or medical condition (including uncontrolled diabetes mellitus)
- •Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on these treatments) (see Annex 1 and Annex 2)
- •Concomitant vaccination with yellow fever vaccine
研究组 & 干预措施
Arm 1
patients with advanced Adrenocortical- Carcinoma progressing after previous chemotherapy lines will be treated with Cabazitaxel
干预措施: Cabazitaxel (Drug)
结局指标
主要结局
To assess the clinical benefit after 4 months of the cabazitaxel in patients with locally advanced or metastatic ACC who progressed after cytotoxic therapy.
时间窗: 4 months
CT scan evaluated according to RECIST 1.1 criteria
次要结局
- Assessment of Objective Response Rates (ORR)(Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year)
- Assessment of overall survival(Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year)
- Assessment of quality of life(Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year)
- Assessment of toxicity(Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year)
- Assessment of hormone response(Every cycle (21 days) for a maximum of 6 cycles and for 6 months follow up. Total 1 year)
研究者
Alfredo Berruti
MD
Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia