Cushing SyndromePhase 2ABACUSNCT03145285
Activity of Abiraterone Acetate in the Management of Cushing's Syndrome in Patients With Adrenocortical Carcinoma
A Phase 2 study testing Abiraterone Acetate in people with Cushing Syndrome and Adrenocortical Carcinoma, run by Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cushing Syndrome, Adrenocortical Carcinoma
- What is being tested?
- Abiraterone Acetate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteItaly
- Study dates
- 18 Apr 2017to 18 Apr 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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;
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- ECOG performance status ≤ 2
- Effective contraception
- Patients must provide verbal and written informed consent to be enrolled in the study
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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.
Read the detailed description
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.
- Conditions
- Cushing Syndrome, Adrenocortical Carcinoma
- Being tested
- Abiraterone Acetate
- Keywords
- Abiraterone Acetate, Cushing Syndrome, Adrenocortical Carcinoma
- Medical subject headings
- Cushing Syndrome, Adrenocortical Carcinoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Abiraterone AcetateDrug
Also called Zytiga
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.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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. Receives: Drug: Abiraterone Acetate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
laboratory tests
Measured: 1 month
time to reduction of UFC (compared to screening values)
laboratory tests (24-h UFC excretion)
Measured: 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
laboratory tests
Measured: 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
multiparameter scoring based on clinical signs/and symptoms and biochemical alterations associated to hypercortisolism
Measured: every visit up to 48 months
improvement of quality of life
evaluation of validated questionnaire (FACT-G)
Measured: every visit up to 48 months
safety and tolerability of oral assumption of AA
evaluation of side effects appearance with study drug using the National Cancer Institute Common Toxicity Criteria (NCI-CTCAE)
Measured: 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)
CT total body or MRI scan or FDG PET
Measured: every 3 months or earlier upon clinician's decision, up to 48 months
progression-free survival
defined as the time elapsing from patient registration to first evidence of disease progression
Measured: every visit up to 48 months
time to syndrome relapse
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
Measured: every visit up to 48 months
overall survival
defined as months from the first day of drug administration to the end of follow up or patient's death
Measured: every visit up to 48 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 May 2017
- Study start18 Apr 2017
- Primary completion18 Apr 2020 (estimated)
- Study completion18 Apr 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Cushing SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 10 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
- Sponsor type
- University, hospital or other
- Collaborators
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Niguarda Hospital, San Camillo Hospital, Rome, San Luigi Gonzaga Hospital
- Responsible party
- Principal investigator, Salvatore Grisanti, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
- Investigators
- Salvatore Grisanti, MD, PhD, Principal investigator, Asst Degli Spedali Civili Di Brescia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03145285
- Sponsor's protocol ID
- ASSTBS-ONCO-ABACUS-16
- Other IDs
- 2016-000945-29, 2016
- Acronym
- ABACUS
- Status last verified
- May 2017
- First submitted
- 26 Apr 2017
- Last updated
- 10 May 2017
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Berruti A, Baudin E, Gelderblom H, Haak HR, Porpiglia F, Fassnacht M, Pentheroudakis G; ESMO Guidelines Working Group. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012 Oct;23 Suppl 7:vii131-8. doi: 10.1093/annonc/mds231. No abstract available.
PubMed 22997446Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, Dousset B, Bertagna X, Bertherat J. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab. 2006 Jul;91(7):2650-5. doi: 10.1210/jc.2005-2730. Epub 2006 May 2.
PubMed 16670169Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005 Sep;12(3):657-66. doi: 10.1677/erc.1.01025.
PubMed 16172198Berruti A, Fassnacht M, Haak H, Else T, Baudin E, Sperone P, Kroiss M, Kerkhofs T, Williams AR, Ardito A, Leboulleux S, Volante M, Deutschbein T, Feelders R, Ronchi C, Grisanti S, Gelderblom H, Porpiglia F, Papotti M, Hammer GD, Allolio B, Terzolo M. Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer. Eur Urol. 2014 Apr;65(4):832-8. doi: 10.1016/j.eururo.2013.11.006. Epub 2013 Nov 14.
PubMed 24268504Daniel E, Aylwin S, Mustafa O, Ball S, Munir A, Boelaert K, Chortis V, Cuthbertson DJ, Daousi C, Rajeev SP, Davis J, Cheer K, Drake W, Gunganah K, Grossman A, Gurnell M, Powlson AS, Karavitaki N, Huguet I, Kearney T, Mohit K, Meeran K, Hill N, Rees A, Lansdown AJ, Trainer PJ, Minder AE, Newell-Price J. Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients. J Clin Endocrinol Metab. 2015 Nov;100(11):4146-54. doi: 10.1210/jc.2015-2616. Epub 2015 Sep 9.
PubMed 26353009Dharia S, Slane A, Jian M, Conner M, Conley AJ, Parker CR Jr. Colocalization of P450c17 and cytochrome b5 in androgen-synthesizing tissues of the human. Biol Reprod. 2004 Jul;71(1):83-8. doi: 10.1095/biolreprod.103.026732. Epub 2004 Feb 25.
PubMed 14985252de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Flechon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. doi: 10.1056/NEJMoa1014618.
PubMed 21612468Trump DL. Commentary on "Abiraterone in metastatic prostate cancer without previous chemotherapy." Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators, Genitourinary Medical Oncology Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA. N Engl J Med 2013;368(2):138-48 [Epub 2012 Dec 10]; N Engl J Med 2013;368(6):584. Urol Oncol. 2013 Nov;31(8):1846. doi: 10.1016/j.urolonc.2013.08.012.
PubMed 24210085Ang JE, Olmos D, de Bono JS. CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer. Br J Cancer. 2009 Mar 10;100(5):671-5. doi: 10.1038/sj.bjc.6604904. Epub 2009 Feb 17.
PubMed 19223900Yap TA, Carden CP, Attard G, de Bono JS. Targeting CYP17: established and novel approaches in prostate cancer. Curr Opin Pharmacol. 2008 Aug;8(4):449-57. doi: 10.1016/j.coph.2008.06.004. Epub 2008 Jul 28.
PubMed 18619560Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009 Apr;23(2):181-92. doi: 10.1016/j.beem.2008.10.014.
PubMed 19500762Ferraldeschi R, Sharifi N, Auchus RJ, Attard G. Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer. Clin Cancer Res. 2013 Jul 1;19(13):3353-9. doi: 10.1158/1078-0432.CCR-12-0931. Epub 2013 Mar 7.
PubMed 23470964Baudin E, Pellegriti G, Bonnay M, Penfornis A, Laplanche A, Vassal G, Schlumberger M. Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p'DDD) levels on the treatment of patients with adrenocortical carcinoma. Cancer. 2001 Sep 15;92(6):1385-92. doi: 10.1002/1097-0142(20010915)92:63.0.co;2-2.
PubMed 11745214van Erp NP, Guchelaar HJ, Ploeger BA, Romijn JA, Hartigh Jd, Gelderblom H. Mitotane has a strong and a durable inducing effect on CYP3A4 activity. Eur J Endocrinol. 2011 Apr;164(4):621-6. doi: 10.1530/EJE-10-0956. Epub 2011 Jan 10.
PubMed 21220434Chung E, Nafziger AN, Kazierad DJ, Bertino JS Jr. Comparison of midazolam and simvastatin as cytochrome P450 3A probes. Clin Pharmacol Ther. 2006 Apr;79(4):350-61. doi: 10.1016/j.clpt.2005.11.016. Epub 2006 Feb 28.
PubMed 16580903
Study at a glance
From the registry record, last updated by the sponsor on 10 May 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Activity of Abiraterone Acetate in the Management of Cushing's Syndrome in Patients With Adrenocortical Carcinoma
- ClinicalTrials.gov ID
- NCT03145285
- Acronym / sponsor ID
- ABACUS / ASSTBS-ONCO-ABACUS-16
- Conditions
- Cushing Syndrome, Adrenocortical Carcinoma
- Keywords
- Abiraterone Acetate, Cushing Syndrome, Adrenocortical Carcinoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 10 participants (estimated)
- Lead sponsor
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di BresciaUniversity, hospital or other
- Collaborators
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Niguarda Hospital, San Camillo Hospital, Rome, San Luigi Gonzaga Hospital
- Study start
- 18 Apr 2017 (actual)
- Primary completion
- 18 Apr 2020 (estimated)
- Study completion
- 18 Apr 2021 (estimated)
- First posted
- 9 May 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Experimental | Drug: Abiraterone AcetatePatients locally advanced/metastatic ACC patients with uncontrolled Cushing's syndrome despite Mitotane +/- chemotherapy. Treatment with single agent Abiraterone Acetate (AA) until progression |
| Cohort 2 | Experimental | Drug: Abiraterone AcetateMitotane-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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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;
Key exclusion criteria (12 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Abiraterone AcetateAlso: ZytigaCohort 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. | Drug | Cohort 1, Cohort 2 |
Primary outcome
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
10 secondary outcomes
to assess the activity of AA in attaining 50% reduction of 24-h UFC excretion within 1 month of treatment
Time frame: 1 month
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.
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
improvement of the clinical signs associated to hypercortisolism
Time frame: every visit up to 48 months
improvement of quality of life
Time frame: every visit up to 48 months
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
treatment response (according to RECIST criteria)
Time frame: every 3 months or earlier upon clinician's decision, up to 48 months
progression-free survival
Time frame: every visit up to 48 months
time to syndrome relapse
Time frame: every visit up to 48 months
overall survival
Time frame: every visit up to 48 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 May 2017.
- Results publication: PubMed 22997446Berruti A, Baudin E, Gelderblom H, Haak HR, Porpiglia F, Fassnacht M, Pentheroudakis G; ESMO Guidelines Working Group. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012 Oct;23 Suppl 7:vii131-8. doi: 10.1093/annonc/mds231. No abstract available.
- Results publication: PubMed 16670169Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, Dousset B, Bertagna X, Bertherat J. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab. 2006 Jul;91(7):2650-5. doi: 10.1210/jc.2005-2730. Epub 2006 May 2.
- Results publication: PubMed 16172198Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005 Sep;12(3):657-66. doi: 10.1677/erc.1.01025.
- Results publication: PubMed 24268504Berruti A, Fassnacht M, Haak H, Else T, Baudin E, Sperone P, Kroiss M, Kerkhofs T, Williams AR, Ardito A, Leboulleux S, Volante M, Deutschbein T, Feelders R, Ronchi C, Grisanti S, Gelderblom H, Porpiglia F, Papotti M, Hammer GD, Allolio B, Terzolo M. Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer. Eur Urol. 2014 Apr;65(4):832-8. doi: 10.1016/j.eururo.2013.11.006. Epub 2013 Nov 14.
- Results publication: PubMed 26353009Daniel E, Aylwin S, Mustafa O, Ball S, Munir A, Boelaert K, Chortis V, Cuthbertson DJ, Daousi C, Rajeev SP, Davis J, Cheer K, Drake W, Gunganah K, Grossman A, Gurnell M, Powlson AS, Karavitaki N, Huguet I, Kearney T, Mohit K, Meeran K, Hill N, Rees A, Lansdown AJ, Trainer PJ, Minder AE, Newell-Price J. Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients. J Clin Endocrinol Metab. 2015 Nov;100(11):4146-54. doi: 10.1210/jc.2015-2616. Epub 2015 Sep 9.
- Results publication: PubMed 14985252Dharia S, Slane A, Jian M, Conner M, Conley AJ, Parker CR Jr. Colocalization of P450c17 and cytochrome b5 in androgen-synthesizing tissues of the human. Biol Reprod. 2004 Jul;71(1):83-8. doi: 10.1095/biolreprod.103.026732. Epub 2004 Feb 25.
- Results publication: PubMed 21612468de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Flechon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. doi: 10.1056/NEJMoa1014618.
- Results publication: PubMed 24210085Trump DL. Commentary on "Abiraterone in metastatic prostate cancer without previous chemotherapy." Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators, Genitourinary Medical Oncology Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA. N Engl J Med 2013;368(2):138-48 [Epub 2012 Dec 10]; N Engl J Med 2013;368(6):584. Urol Oncol. 2013 Nov;31(8):1846. doi: 10.1016/j.urolonc.2013.08.012.
- Results publication: PubMed 19223900Ang JE, Olmos D, de Bono JS. CYP17 blockade by abiraterone: further evidence for frequent continued hormone-dependence in castration-resistant prostate cancer. Br J Cancer. 2009 Mar 10;100(5):671-5. doi: 10.1038/sj.bjc.6604904. Epub 2009 Feb 17.
- Results publication: PubMed 18619560Yap TA, Carden CP, Attard G, de Bono JS. Targeting CYP17: established and novel approaches in prostate cancer. Curr Opin Pharmacol. 2008 Aug;8(4):449-57. doi: 10.1016/j.coph.2008.06.004. Epub 2008 Jul 28.
- Results publication: PubMed 19500762Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009 Apr;23(2):181-92. doi: 10.1016/j.beem.2008.10.014.
- Results publication: PubMed 23470964Ferraldeschi R, Sharifi N, Auchus RJ, Attard G. Molecular pathways: Inhibiting steroid biosynthesis in prostate cancer. Clin Cancer Res. 2013 Jul 1;19(13):3353-9. doi: 10.1158/1078-0432.CCR-12-0931. Epub 2013 Mar 7.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Salvatore Grisanti, MD, PhD principal investigator
Asst Degli Spedali Civili Di Brescia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Abiraterone Acetate in people with Cushing Syndrome and Adrenocortical Carcinoma, run by Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 10 May 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03145285, which also lists 15 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 May 2017.