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

NCT03145285 | Unknown Phase 2 DMC

• 2 other identifiers: ASSTBS-ONCO-ABACUS-162016-000945-29
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Cushing Syndrome; Adrenocortical Carcinoma

Keywords

Abiraterone Acetate; Cushing Syndrome; Adrenocortical Carcinoma

Outcome Measures

Primary Outcomes (1)

• 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

  laboratory tests

  1 month

Secondary Outcomes (10)

• to assess the activity of AA in attaining 50% reduction of 24-h UFC excretion within 1 month of treatment

  1 month

• 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.

• 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

• improvement of the clinical signs associated to hypercortisolism

  every visit up to 48 months

• improvement of quality of life

  every visit up to 48 months

Study Arms (2)

Cohort 1

EXPERIMENTAL

Patients locally advanced/metastatic ACC patients with uncontrolled Cushing's syndrome despite Mitotane +/- chemotherapy. Treatment with single agent Abiraterone Acetate (AA) until progression

Drug: Abiraterone Acetate

Cohort 2

EXPERIMENTAL

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.

Drug: Abiraterone Acetate

Interventions

Abiraterone Acetate DRUG

Cohort 1: Patients locally advanced/metastatic ACC patients with uncontrolled Cushing's syndrome despite Mitotane +/- chemotherapy will be treated with single agent AA.Mitotane and chemotherapy will be interrupted and AA will be continued till progression and/or 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 will be treated with 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 (i.e. 2 or 3 weeks from Abiraterone start), then Mitotane +/- chemotherapy can be started upon the clinician's decision.

Also known as: Zytiga

Cohort 1; Cohort 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia: lead
• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: collaborator
• Niguarda Hospital: collaborator
• San Camillo Hospital, Rome: collaborator
• San Luigi Gonzaga Hospital: collaborator

Study Sites (1)

U.O Oncologia Medica

Brescia, BS, 25123, Italy

Location

Related Publications (15)

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MeSH Terms

Conditions

Cushing Syndrome; Adrenocortical Carcinoma

Interventions

Abiraterone Acetate

Condition Hierarchy (Ancestors)

Adrenocortical Hyperfunction; Adrenal Gland Diseases; Endocrine System Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Adrenal Cortex Diseases

Intervention Hierarchy (Ancestors)

Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Salvatore Grisanti, MD, PhD

  ASST Spedali Civili di Brescia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: April 26, 2017
• First Posted: May 9, 2017
• Study Start: April 18, 2017
• Primary Completion: April 18, 2020
• Study Completion: April 18, 2021
• Last Updated: May 10, 2017

Record last verified: 2017-05

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)