Clinical trial NCT05913427: Evaluation of the Efficacy of Addition of Progesterone to Standard Chemotherapy in Adrenocortical Carcinoma (ACC)
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Adrenocortical Carcinoma
Lead sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
Sponsor class: OTHER
First posted: 2023-06-22
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: 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.
timeFrame: 18 months
Secondary outcomes:
measure: Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
timeFrame: 18 months
measure: Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
timeFrame: 18 months
measure: Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
timeFrame: 18 months
measure: Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
timeFrame: 18 months
measure: Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
timeFrame: 18 months
measure: Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
timeFrame: 18 months
measure: Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
timeFrame: 18 months
measure: Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
timeFrame: 18 months
measure: Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
timeFrame: 18 months
measure: Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
timeFrame: 18 months
measure: Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
timeFrame: 18 months
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: Alfredo Berruti
Study officials:
affiliation: ASST Spedali Civili di Brescia
name: Alfredo Berruti
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.