Evaluation of the Efficacy of Addition of Progesterone to Standard Chemotherapy in Adrenocortical Carcinoma (ACC) (PESETA)

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ClinicalTrials.gov Identifier: NCT05913427

Recruitment Status : Recruiting

First Posted : June 22, 2023

Last Update Posted : June 22, 2023

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Sponsor:

Information provided by (Responsible Party):

Alfredo Berruti, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

Study Description

Brief Summary:

This is a prospective randomized, double blind, placebo controlled phase II study planned in patients with advanced ACC. The study will be conducted at ASST Spedali Civili Hospital and University of Brescia in Brescia.

Condition or disease	Intervention/treatment	Phase
Adrenocortical Carcinoma	Drug: Etoposide, doxorubicin, cisplatin and Mitotane plus Megestrol Acetate 160 MG Drug: Etoposide, doxorubicin, cisplatin and Mitotane plus Placebo	Phase 2

Detailed Description:

As no effective second-line therapies are available for patients with disease progression to EDPM, including modern molecular target therapies and immunotherapy, it is reasonable to expect that no newer drugs or combination regimens will be able to replace EDPM in the next 5 years. Since EDP-M is destined to remain the standard first line therapy, research strategies aimed to improve the efficacy of this regimen are of relevance. In this study, investigators will address the hypotheses that progesterone has a synergistic and/or additive effect to EDP-M in inducing cytotoxicity in ACC cells in vitro and the antineoplastic activity of EDP-M in locally advanced/metastatic ACC patients could be improved by the addition of megestrol acetate.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	80 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	Prospective, Phase II Study to Evaluate the Efficacy of Addition of Progesterone to Standard Chemotherapy According to Etoposide-Doxorubicin-Cisplatin Scheme Plus Mitotane (EDP-M) in Patients With Advanced Adrenocortical Carcinoma (ACC)
Actual Study Start Date :	June 8, 2022
Estimated Primary Completion Date :	June 8, 2027
Estimated Study Completion Date :	June 8, 2027

Resource links provided by the National Library of Medicine

Drug Information available for: Mitotane Megestrol acetate Cisplatin Doxorubicin Doxorubicin hydrochloride Etoposide Etoposide phosphate

Genetic and Rare Diseases Information Center resources: Adrenocortical Carcinoma

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: EDP-M plus MEGESTROL ACETATE 160 mg EDP will be administered at the following doses: doxorubicin 40 mg/m2 on day 1, etoposide 100 mg/m2 days 2-4, cisplatin 40 mg/m2 days 3-4, every 28 days. Concomitant mitotane therapy will be administered continuously. Megestrole 160 mg 2 tablets will be administered once daily (in the morning) and will be stopped 21 days after the last administration of the EDP.	Drug: Etoposide, doxorubicin, cisplatin and Mitotane plus Megestrol Acetate 160 MG EDP will be administered at the following doses: doxorubicin 40 mg/m2 on day 1, etoposide 100 mg/m2 days 2-4, cisplatin 40 mg/m2 days 3-4, every 28 days. Megestrol acetate will be prepared and packaged by the authorized external contract development and manufacturing organization (CDMO) Doppel Farmaceutici s.r.l. (Cortemaggiore, PC), that, according to the GMP and applicable law (FU XII ed) will also prepare the related placebo, in accordance with GMP (annex 13) and applicable law (FU XII ed.). Other Name: Megace
Placebo Comparator: EDP-M plus PLACEBO EDP will be administered at the following doses: doxorubicin 40 mg/m2 on day 1, etoposide 100 mg/m2 days 2-4, cisplatin 40 mg/m2 days 3-4, every 28 days. Concomitant mitotane therapy will be administered continuously. Placebo 2 tablets will be administered once daily (in the morning) and will be stopped 21 days after the last administration of the EDP.	Drug: Etoposide, doxorubicin, cisplatin and Mitotane plus Placebo EDP will be administered at the following doses: doxorubicin 40 mg/m2 on day 1, etoposide 100 mg/m2 days 2-4, cisplatin 40 mg/m2 days 3-4, every 28 days. Placebo 160 mg tablets will be developed by the CDMO to have the same appearance and taste as the tablet containing the active drug. Other Name: placebo

Arm

Intervention/treatment

Experimental: EDP-M plus MEGESTROL ACETATE 160 mg

EDP will be administered at the following doses: doxorubicin 40 mg/m2 on day 1, etoposide 100 mg/m2 days 2-4, cisplatin 40 mg/m2 days 3-4, every 28 days. Concomitant mitotane therapy will be administered continuously. Megestrole 160 mg 2 tablets will be administered once daily (in the morning) and will be stopped 21 days after the last administration of the EDP.

Drug: Etoposide, doxorubicin, cisplatin and Mitotane plus Megestrol Acetate 160 MG

EDP will be administered at the following doses: doxorubicin 40 mg/m2 on day 1, etoposide 100 mg/m2 days 2-4, cisplatin 40 mg/m2 days 3-4, every 28 days.

Megestrol acetate will be prepared and packaged by the authorized external contract development and manufacturing organization (CDMO) Doppel Farmaceutici s.r.l. (Cortemaggiore, PC), that, according to the GMP and applicable law (FU XII ed) will also prepare the related placebo, in accordance with GMP (annex 13) and applicable law (FU XII ed.).

Other Name: Megace

Placebo Comparator: EDP-M plus PLACEBO

EDP will be administered at the following doses: doxorubicin 40 mg/m2 on day 1, etoposide 100 mg/m2 days 2-4, cisplatin 40 mg/m2 days 3-4, every 28 days. Concomitant mitotane therapy will be administered continuously. Placebo 2 tablets will be administered once daily (in the morning) and will be stopped 21 days after the last administration of the EDP.

Drug: Etoposide, doxorubicin, cisplatin and Mitotane plus Placebo

EDP will be administered at the following doses: doxorubicin 40 mg/m2 on day 1, etoposide 100 mg/m2 days 2-4, cisplatin 40 mg/m2 days 3-4, every 28 days. Placebo 160 mg tablets will be developed by the CDMO to have the same appearance and taste as the tablet containing the active drug.

Other Name: placebo

Outcome Measures

Primary Outcome Measures :

Evaluation of the activity of the combination regimen (EDP-M plus progesterone (EDP-MP) versus EDP-M plus placebo) in advanced/ metastatic patients with ACC. [ Time Frame: 18 months ]
Comparison of proportion of patients attaining an Objective Response (Objective Response Rate, ORR), evaluated by RECIST criteria between the 2 treatment arms.

Secondary Outcome Measures :

Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; [ Time Frame: 18 months ]
Changes in serum cortisol from baseline in the two treatment arms;
Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; [ Time Frame: 18 months ]
Changes in serum UFC from baseline in the two treatment arms;
Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; [ Time Frame: 18 months ]
Changes in serum salivary cortisol from baseline in the two treatment arms;
Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; [ Time Frame: 18 months ]
Changes in ACTH from baseline in the two treatment arms;
Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; [ Time Frame: 18 months ]
Changes in serum 11-deoxycortisol from baseline in the two treatment arms;
Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; [ Time Frame: 18 months ]
Changes in serum aldosterone from baseline in the two treatment arms;
Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; [ Time Frame: 18 months ]
Changes in serum PRA from baseline in the two treatment arms;
Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; [ Time Frame: 18 months ]
Changes in serum androstenedione from baseline in the two treatment arms;
Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; [ Time Frame: 18 months ]
Changes in serum DHEA-S from baseline in the two treatment arms;
Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; [ Time Frame: 18 months ]
Changes in serum progesterone from baseline in the two treatment arms;
Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; [ Time Frame: 18 months ]
Changes in serum total testosterone from baseline in the two treatment arms;

Eligibility Criteria

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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
Locally advanced or metastatic disease not amenable to radical surgery resection
ECOG performance status 0-2
Effective contraception
Life expectancy > 3 months
Age > 18 years
Adequate bone marrow reserve (neutrophils >1,000/mm3 and/or platelets >80,000/mm3) and organ function (including renal, liver and cardiac function)
Be able to comply with the protocol procedures and provide written informed consent.

Exclusion Criteria:

History of recent or active prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, breast ductal carcinoma in situ, or other treated malignancies where there has been no evidence of disease for at least 2 years
Renal insufficiency (estimated glomerular filtration rate [GFR]<50 mL/min/1.73 m2) or significant liver insufficiency (serum bilirubin>2 times the upper normal range and/or serum alanine aminotransferase [ALT] or aspartate aminotransferase [AST]>3 times the upper normal range). GFRs will be calculated according to the validated formula (MDRD)
Pregnancy or breast feeding
Congestive heart failure (ejection fraction<45%)
Preexisting grade 2 peripheral neuropathy
Previous or current treatment with mitotane or other antineoplastic drugs for ACC
Previous radiotherapy for ACC
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 that, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Contacts and Locations

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): NCT05913427

Contacts

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Contact: Aldo Roccaro	+390303996851	coordinamento.ricerca@asst-spedalicivili.it

Locations

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Italy
Alfredo Berruti	Recruiting
Brescia, Italy, 25123
Contact: Alfredo Berruti +390303995260 alfredo.berruti@gmail.com

Sponsors and Collaborators

Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

Investigators

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Principal Investigator:	Alfredo Berruti	ASST Spedali Civili di Brescia

More Information

Publications of Results:

Fassnacht M, Assie G, Baudin E, Eisenhofer G, de la Fouchardiere C, Haak HR, de Krijger R, Porpiglia F, Terzolo M, Berruti A; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Nov;31(11):1476-1490. doi: 10.1016/j.annonc.2020.08.2099. Epub 2020 Aug 27. No abstract available. Erratum In: Ann Oncol. 2023 Jul;34(7):631.

Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardiere C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Muller HH, Skogseid B; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-97. doi: 10.1056/NEJMoa1200966. Epub 2012 May 2.

Fiorentini C, Fragni M, Perego P, Vezzoli S, Bonini SA, Tortoreto M, Galli D, Claps M, Tiberio GA, Terzolo M, Missale C, Memo M, Procopio G, Zaffaroni N, Berruti A, Sigala S. Antisecretive and Antitumor Activity of Abiraterone Acetate in Human Adrenocortical Cancer: A Preclinical Study. J Clin Endocrinol Metab. 2016 Dec;101(12):4594-4602. doi: 10.1210/jc.2016-2414. Epub 2016 Sep 14.

Fragni M, Fiorentini C, Rossini E, Fisogni S, Vezzoli S, Bonini SA, Dalmiglio C, Grisanti S, Tiberio GAM, Claps M, Cosentini D, Salvi V, Bosisio D, Terzolo M, Missale C, Facchetti F, Memo M, Berruti A, Sigala S. In vitro antitumor activity of progesterone in human adrenocortical carcinoma. Endocrine. 2019 Mar;63(3):592-601. doi: 10.1007/s12020-018-1795-x. Epub 2018 Oct 26.

Rossini E, Tamburello M, Abate A, Beretta S, Fragni M, Cominelli M, Cosentini D, Hantel C, Bono F, Grisanti S, Poliani PL, Tiberio GAM, Memo M, Sigala S, Berruti A. Cytotoxic Effect of Progesterone, Tamoxifen and Their Combination in Experimental Cell Models of Human Adrenocortical Cancer. Front Endocrinol (Lausanne). 2021 Apr 26;12:669426. doi: 10.3389/fendo.2021.669426. eCollection 2021.

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Responsible Party:	Alfredo Berruti, Medical Oncologist, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
ClinicalTrials.gov Identifier:	NCT05913427
Other Study ID Numbers:	ASSTBS-FARONCO- PESETA-20
First Posted:	June 22, 2023 Key Record Dates
Last Update Posted:	June 22, 2023
Last Verified:	January 2023
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

Additional relevant MeSH terms:

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Carcinoma Adrenocortical Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Adenocarcinoma Adrenal Cortex Neoplasms Adrenal Gland Neoplasms Endocrine Gland Neoplasms Neoplasms by Site Adrenal Cortex Diseases Adrenal Gland Diseases Endocrine System Diseases Cisplatin Doxorubicin	Liposomal doxorubicin Etoposide Etoposide phosphate Megestrol Megestrol Acetate Mitotane Antineoplastic Agents Antibiotics, Antineoplastic Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Phytogenic Contraceptives, Oral, Hormonal Contraceptives, Oral

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