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.
Histologically confirmed diagnosis of ACC
Locally advanced or metastatic disease not amenable to radical surgery resection
ECOG performance status 0-2
Effective contraception
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%)
Parallel
Etoposide, doxorubicin, cisplatin and Mitotane plus Megestrol Acetate 160 MG
DrugEDP 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.).
Etoposide, doxorubicin, cisplatin and Mitotane plus Placebo
DrugEDP 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.
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.
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;
Evaluation of the impact of the combination of the two treatments on hormone response in patients with secreting ACC;
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;
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;
Changes in ACTH from baseline in the two treatment arms;
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