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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| EDP-M plus MEGESTROL ACETATE 160 mg | Experimental | 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. |
|
| EDP-M plus PLACEBO | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Etoposide, doxorubicin, cisplatin and Mitotane plus Megestrol Acetate 160 MG | Drug | 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.). |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Comparison of proportion of patients attaining an Objective Response (Objective Response Rate, ORR), evaluated by RECIST criteria between the 2 treatment arms. | 18 months |
| Measure | Description | Time Frame |
|---|---|---|
| Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; | Changes in serum cortisol from baseline in the two treatment arms; | 18 months |
| Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Aldo Roccaro | Contact | +390303996851 | coordinamento.ricerca@asst-spedalicivili.it |
| Name | Affiliation | Role |
|---|---|---|
| Alfredo Berruti | Asst Degli Spedali Civili Di Brescia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Alfredo Berruti | Recruiting | Brescia | 25123 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32861807 | Result | 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. | |
| 22551107 |
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|
|
| Etoposide, doxorubicin, cisplatin and Mitotane plus Placebo | Drug | 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. |
|
|
Changes in serum UFC from baseline in the two treatment arms; |
| 18 months |
| Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; | Changes in serum salivary cortisol from baseline in the two treatment arms; | 18 months |
| Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; | Changes in ACTH from baseline in the two treatment arms; | 18 months |
| Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; | Changes in serum 11-deoxycortisol from baseline in the two treatment arms; | 18 months |
| Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; | Changes in serum aldosterone from baseline in the two treatment arms; | 18 months |
| Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; | Changes in serum PRA from baseline in the two treatment arms; | 18 months |
| Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; | Changes in serum androstenedione from baseline in the two treatment arms; | 18 months |
| Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; | Changes in serum DHEA-S from baseline in the two treatment arms; | 18 months |
| Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; | Changes in serum progesterone from baseline in the two treatment arms; | 18 months |
| Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC; | Changes in serum total testosterone from baseline in the two treatment arms; | 18 months |
| Result |
| 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. |
| 27626976 | Result | 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. |
| 30367443 | Result | 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. |
| 33981288 | Result | 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. |
| ID | Term |
|---|---|
| D018268 | Adrenocortical Carcinoma |
| ID | Term |
|---|---|
| D000230 | Adenocarcinoma |
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D000306 | Adrenal Cortex Neoplasms |
| D000310 | Adrenal Gland Neoplasms |
| D004701 | Endocrine Gland Neoplasms |
| D009371 | Neoplasms by Site |
| D000303 | Adrenal Cortex Diseases |
| D000307 | Adrenal Gland Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D005047 | Etoposide |
| D004317 | Doxorubicin |
| D002945 | Cisplatin |
| D008939 | Mitotane |
| D019290 | Megestrol Acetate |
| ID | Term |
|---|---|
| D011034 | Podophyllotoxin |
| D013764 | Tetrahydronaphthalenes |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D005960 | Glucosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D003630 | Daunorubicin |
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D000617 | Aminoglycosides |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017672 | Nitrogen Compounds |
| D017671 | Platinum Compounds |
| D006843 | Hydrocarbons, Chlorinated |
| D006846 | Hydrocarbons, Halogenated |
| D008535 | Megestrol |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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