Activity of Abiraterone Acetate in the Management of Cushing's Syndrome in Patients With Adrenocortical Carcinoma

• Status: Unknown status
• Trial end date: 2021-04-18
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Azienda Ospedaliera Spedali Civili di Brescia; Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
• Collaborators: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; Niguarda Hospital; San Camillo Hospital, Rome; San Luigi Gonzaga Hospital
• Treatments: Abiraterone Acetate; Mitotane

Criteria

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