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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Adrenocortical Carcinoma

Intervention / Treatment
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* Drug: Etoposide, doxorubicin, cisplatin and Mitotane plus Megestrol Acetate 160 MG
* Drug: Etoposide, doxorubicin, cisplatin and Mitotane plus Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EDP-M plus MEGESTROL ACETATE 160 mg<br>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<br>* 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.).<br>* Other names: Megace;|
| Placebo Comparator: EDP-M plus PLACEBO<br>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<br>* 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.<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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; | 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 |