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

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ClinicalTrials.gov Identifier: NCT03145285
Recruitment Status : Active, not recruiting
First Posted : May 9, 2017
Last Update Posted : May 10, 2017
Sponsor:
Collaborators:
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Niguarda Hospital
San Camillo Hospital, Rome
San Luigi Gonzaga Hospital
Information provided by (Responsible Party):
Salvatore Grisanti, Azienda Ospedaliera Spedali Civili di Brescia

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.


Condition or disease Intervention/treatment Phase
Cushing Syndrome Adrenocortical Carcinoma Drug: Abiraterone Acetate Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Activity of Abiraterone Acetate in the Management of Cushing's Syndrome in Patients With Adrenocortical Carcinoma
Actual Study Start Date : April 18, 2017
Estimated Primary Completion Date : April 18, 2020
Estimated Study Completion Date : April 18, 2021


Arm Intervention/treatment
Experimental: 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

Drug: Abiraterone Acetate

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.

Other Name: Zytiga

Experimental: 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.

Drug: Abiraterone Acetate

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.

Other Name: Zytiga




Primary Outcome Measures :
  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 [ Time Frame: 1 month ]
    laboratory tests


Secondary Outcome Measures :
  1. to assess the activity of AA in attaining 50% reduction of 24-h UFC excretion within 1 month of treatment [ Time Frame: 1 month ]
    laboratory tests

  2. time to reduction of UFC (compared to screening values) [ Time Frame: Weekly, from date of treatment start, for the first month; thereafter every 2 months up to 48 months. ]
    laboratory tests (24-h UFC excretion)

  3. effect of AA on levels of serum cortisol, UFC, salivary cortisol, ACTH, aldosterone, PRA, DHEA-S, total testosterone, and steroid precursors [ Time Frame: Monthly, from date of treatment start, for the first 3 months; thereafter every 2 months up to 48 months ]
    laboratory tests

  4. improvement of the clinical signs associated to hypercortisolism [ Time Frame: every visit up to 48 months ]
    multiparameter scoring based on clinical signs/and symptoms and biochemical alterations associated to hypercortisolism

  5. improvement of quality of life [ Time Frame: every visit up to 48 months ]
    evaluation of validated questionnaire (FACT-G)

  6. safety and tolerability of oral assumption of AA [ Time Frame: 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 ]
    evaluation of side effects appearance with study drug using the National Cancer Institute Common Toxicity Criteria (NCI-CTCAE)

  7. treatment response (according to RECIST criteria) [ Time Frame: every 3 months or earlier upon clinician's decision, up to 48 months ]
    CT total body or MRI scan or FDG PET

  8. progression-free survival [ Time Frame: every visit up to 48 months ]
    defined as the time elapsing from patient registration to first evidence of disease progression

  9. time to syndrome relapse [ Time Frame: every visit up to 48 months ]
    defined as the time elapsing from the best syndrome control within the first month to relapse of syndrome defined as: 1) Cushing symptoms recurrence; 2) increase more than 50% of nadir cortisol levels

  10. overall survival [ Time Frame: every visit up to 48 months ]
    defined as months from the first day of drug administration to the end of follow up or patient's death



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03145285


Locations
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Italy
U.O Oncologia Medica
Brescia, BS, Italy, 25123
Sponsors and Collaborators
Azienda Ospedaliera Spedali Civili di Brescia
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Niguarda Hospital
San Camillo Hospital, Rome
San Luigi Gonzaga Hospital
Investigators
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Principal Investigator: Salvatore Grisanti, MD, PhD ASST Spedali Civili di Brescia

Publications of Results:

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Responsible Party: Salvatore Grisanti, MD, PhD, Azienda Ospedaliera Spedali Civili di Brescia
ClinicalTrials.gov Identifier: NCT03145285     History of Changes
Other Study ID Numbers: ASSTBS-ONCO-ABACUS-16
2016-000945-29 ( EudraCT Number )
First Posted: May 9, 2017    Key Record Dates
Last Update Posted: May 10, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Salvatore Grisanti, Azienda Ospedaliera Spedali Civili di Brescia:
Abiraterone Acetate
Cushing Syndrome
Adrenocortical Carcinoma

Additional relevant MeSH terms:
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Syndrome
Carcinoma
Cushing Syndrome
Adrenocortical Carcinoma
Disease
Pathologic Processes
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adrenocortical Hyperfunction
Adrenal Gland Diseases
Endocrine System Diseases
Adenocarcinoma
Adrenal Cortex Neoplasms
Adrenal Gland Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Adrenal Cortex Diseases
Abiraterone Acetate
Mitotane
Antineoplastic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 Enzyme Inhibitors
Antineoplastic Agents, Hormonal