Activity of Abiraterone Acetate in the Management of Cushing's Syndrome in Patients With Adrenocortical Carcinoma
试验速览
- 阶段
- 2 期
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- To assess the activity of AA in attaining normalization of 24-h urinary free cortisol (UFC) excretion relative to baseline within 1 month from treatment start
研究概览
简要总结
Adrenocortical Carcinoma (ACC) is an extremely rare disease. Approximately 50% of ACC in adults are functioning leading to hormonal and metabolic syndromes. Cortisol hypersecretion (Cushing's syndrome) is the most common endocrine derangement at presentation. Moreover, hypercortisolism is one of the factors that negatively influence the outcome of patients with metastatic ACC.
Abiraterone acetate (AA) is a prodrug of abiraterone, an irreversible inhibitor of 17α hydroxylase/C17, 20-lyase (cytochrome P450c17 [CYP17]).The inhibition of CYP17A1 blocks androgen and cortisol synthesis. AA has a pharmacodynamic potential to reduce cortisol excess and it has never been tested before in Cushing's syndrome.
Thus, we decided to evaluate the activity of Abiraterone Acetate in the management of Cushing's syndrome in patients with adrenocortical carcinoma. The study is a phase II, non-randomized, open-label study with two different experimental sub-cohorts:
Cohort 1: Patients locally advanced/metastatic ACC patients with uncontrolled Cushing's syndrome despite Mitotane +/- chemotherapy will be treated with single agent AA. In this cohort, Mitotane and chemotherapy will be interrupted and AA will be continued till progression and/or as long as the Cushing's syndrome is adequately controlled (ie until progression of Cushing's syndrome).
Cohort 2: Mitotane-naïve patients with newly diagnosis of ACC associated with Cushing's syndrome not amenable to surgical resection with radical intent will be treated with single agent AA for 4 weeks followed by AA + Mitotane +/- first-line chemotherapy. In this cohort, AA in association with Mitotane will be administered for 3 months. If the primary endpoint is obtained before 1 month (i.e. 2 or 3 weeks from Abiraterone start), then Mitotane +/- chemotherapy can be started upon the clinician's decision.
详细描述
Background:
ACC is an extremely rare disease. About 30% of patients are diagnosed with locally/advanced metastatic disease and about 50-80% of patients who undergo radical resection are destined to relapse often with distant metastases. Approximately 50% of ACC in adults are functioning leading to hormonal and metabolic syndromes. Cortisol hypersecretion (Cushing's syndrome) is the most common endocrine derangement at presentation. Control of the syndrome is mainly obtained by mitotane therapy, however this drug requires several weeks to months for attaining a therapeutic range of serum concentrations. Hypercortisolism is one of the factors that negatively influence the outcome of patients with metastatic ACC.
Abiraterone acetate (AA) is a prodrug of abiraterone, an irreversible inhibitor of 17α hydroxylase/C17, 20-lyase (cytochrome P450c17 [CYP17]), that are key enzymes required for testosterone synthesis. These enzymes are found in the testes, adrenals and prostate tumors. The inhibition of CYP17A1 blocks androgen and cortisol synthesis. Abiraterone has demonstrated to be able to suppress dehydroepiandrosterone (DHEA), androstenedione and testosterone production in both adrenal and testes and to reduce adrenal cortisol production. For these reasons Abiraterone is registered for clinical use in castrate-resistant prostate cancer (CRPC). The maximum inhibition of CYP17A1 is achieved within 28 days of continuous dosing.
Rationale:
- A rapid control of the Cushing's syndrome is important in patients with ACC.
- AA has a pharmacodynamic potential to reduce cortisol excess and it has never been tested before in Cushing's syndrome.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •CT or MRI evidence of metastatic or locally advanced ACC (ENSAT stage III-IV) unsuitable for radical surgery
- •Age ≥ 18 years
- •Confirmed diagnosis of Cushing's syndrome validated by:
- •two 24 h urinary collections for UFC at least 1.5 times the upper the normal levels, within 2 weeks prior to enrollment;
- •serum ACTH levels lower than the normal range;
- •ECOG performance status ≤ 2
- •Effective contraception
- •Patients must provide verbal and written informed consent to be enrolled in the study
排除标准
- •Life expectancy less than 3 months
- •Liver disease, such as cirrhosis, chronic or persistent active hepatitis or AST/ALT > 2 x ULN, bilirubin >2 x ULN
- •Heart failure (NYHA class III or IV), unstable angina, severe arrhythmia or clinically significant impairment of heart function
- •Major surgical procedure within one month prior entering the study
- •Renal impairment (creatinine clearance < 40 ml/min).
- •WBC <3 x 109 /L; Hb <13 g/dL for men and <12 g/dL for women; platelets <100 x 109 /L
- •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.
- •Pregnant or breast-feeding women
- •History of alcohol or drug abuse
- •History of recent or active 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)
- •Acute or chronic uncontrolled infections
- •Patient non-compliance
研究组 & 干预措施
Cohort 1
Patients locally advanced/metastatic ACC patients with uncontrolled Cushing's syndrome despite Mitotane +/- chemotherapy.
Treatment with single agent Abiraterone Acetate (AA) until progression
干预措施: Abiraterone Acetate (Drug)
Cohort 2
Mitotane-naïve patients with newly diagnosis of ACC associated with Cushing's syndrome not amenable to surgical resection.
Treatment with single agent Abiraterone Acetate (AA) for 4 weeks followed by AA + Mitotane +/- first-line chemotherapy. AA in association with Mitotane will be administered for 3 months. If the primary endpoint is obtained before 1 month, then Mitotane +/- chemotherapy can be started upon the clinician's decision.
干预措施: Abiraterone Acetate (Drug)
结局指标
主要结局
To assess the activity of AA in attaining normalization of 24-h urinary free cortisol (UFC) excretion relative to baseline within 1 month from treatment start
时间窗: 1 month
laboratory tests
次要结局
- effect of AA on levels of serum cortisol, UFC, salivary cortisol, ACTH, aldosterone, PRA, DHEA-S, total testosterone, and steroid precursors(Monthly, from date of treatment start, for the first 3 months; thereafter every 2 months up to 48 months)
- progression-free survival(every visit up to 48 months)
- time to reduction of UFC (compared to screening values)(Weekly, from date of treatment start, for the first month; thereafter every 2 months up to 48 months.)
- improvement of quality of life(every visit up to 48 months)
- time to syndrome relapse(every visit up to 48 months)
- overall survival(every visit up to 48 months)
- improvement of the clinical signs associated to hypercortisolism(every visit up to 48 months)
- to assess the activity of AA in attaining 50% reduction of 24-h UFC excretion within 1 month of treatment(1 month)
- safety and tolerability of oral assumption of AA(Weekly, from date of treatment start, for the first month; once a month for the first 3 months; thereafter every 2 months up to 48 months)
- treatment response (according to RECIST criteria)(every 3 months or earlier upon clinician's decision, up to 48 months)
研究者
Salvatore Grisanti
MD, PhD
Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia