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.

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.

Statistical considerations:

The sample size in Cohort 1 according to an Intent To Treat (ITT) procedure is calculated under the following considerations:

H0: current therapies can normalize UFC in 40% of patients in 1 month of therapy; H1: Abiraterone can normalize UFC in at least 70% of patients in 1 month of therapy.

Therefore, the sample size calculation is based on the comparison between the response observed with traditional therapies (R0 = 0.4) and the response expected with the experimental drug (R1 = 0.7). With a two-sided Chi-square test, twenty consecutive patients should be enrolled to detect a 30% absolute difference with an alpha error 5% and a power of 80%.

Considering the exploratory purpose of Cohort 2 substudy, no sample size has been determined and a total of 10 patients will be enrolled.

Abiraterone administration and dose modifications:

Abiraterone Acetate will be administered per os at the standard dose of four 250 mg capsules (1000 mg total dose) daily on an empty stomach in 28-day cycles.

In case of an adverse event (AE) where according to investigator judgement a dose-reduction is required, 1 dose reduction is allowed to 500 mg Abiraterone (4→2 tablets). Any return to protocol dose level (4 tablets) after dose reduction must follow documentation of adverse event resolution.

Safety and management of AEs:

The evaluation period for safety will start from signing of the informed consent form to at least 30 days after the last dose of study drug or recovery from all acute toxicities associated with study drug administration. Adverse events including laboratory AEs will be graded and summarized according to the NCI-CTCAE, Version 4.0. The study will include evaluations of safety according to the time points provided in the Time and Events Schedule.

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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