This clinical trial is a single-arm, non-randomized, prospective phase II study.

The study aims to evaluate if the maintenance immunotherapy with cemiplimab in patients with AdrenoCortical Carcinoma (ACC), who obtained disease response or stabilization after first-line chemotherapy, may delay/prevent disease progression.

The study will be conducted at ASST Spedali Civili Hospital, Brescia - Italy.

Adrenocortical carcinoma (ACC) is a rare malignancy affecting around 0.7-2 persons per one million population per year.

The only pharmacological approach approved by FDA and EMA for the treatment of ACC is mitotane, which has an adrenolytic effect causing adrenocortical insufficiency. So, the drug should be administered in association with glucocorticoid replacement for the purpose only of restoring the daily cortisol requirement.

Few therapeutic alternatives are available for metastatic ACC patients failing one to two lines of systemic treatment, so immunotherapy could represent a potential new treatment. The immune checkpoint inhibitors are the most promising immunotherapy agents in cancer pharmacology and have been also investigated in ACC. Bases on results of some clinical studies, immunotherapy has achieved long-term control in a small proportion of patients with metastatic ACC. We need to identify the patient subset destined to benefit most from this therapy and at what point in the therapeutic sequence of adrenal carcinoma should immunotherapy be introduced. We also need to implement strategies to overcome the intrinsic immuno-resistance of ACC.

The current strategy in the management of advanced ACC is the administration of the EDP (etoposide, doxorubicin, cisplatin) scheme associated with mitotane followed by maintenance mitotane in patients not progressing on chemotherapy. Maintenance immunotherapy could be administered in combination with mitotane, enhancing its efficacy. In addition, the powerful adrenolytic effect of mitotane could keep cortisol production inhibited, facilitating the efficacy of immunotherapy.

Maintenance therapy with cemiplimab in ACC patients after first-line chemotherapy may result in enhanced antitumor activity while avoiding potential interactions, including cross-resistance and cumulative toxicity.

Inclusion Criteria:

1. Male and females >18 years of age;

2. Patients with histologically confirmed ACC;

3. Previous induction therapy with EDP-M followed by cytoreductive surgery if indicated;

4. No disease progression after first line 4-6 EDP-M cycles;

5. An ECOG PS of 0, 1;

6. Adequate organ and bone marrow function documented by:

   1. Hemoglobin >9.0 g/dL

   2. ANC >1.5 x 109/L

   3. Platelet count >75 x 109/L

   4. Serum creatinine <1.5 ULN or estimated CrCl >30 mL/min

   5. Adequate hepatic function:

      • Total bilirubin <1.5 x ULN;
      • AST and ALT both <3 x ULN;
      • ALP <2.5 x ULN; Note: For patients with Gilbert's syndrome, total bilirubin ≤3x ULN. Gilbert's syndrome must be documented appropriately as past medical history.

7. Women of child-bearing potential (physiologically capable of becoming pregnant) that must agree to follow instructions for methods of contraception (including at least one highly effective contraception method, see study protocol) for the duration of treatment with study drug, and after discontinuation of treatment as long as mitotane plasma levels are detectable and, in any case, at least for 6 months post treatment completion; must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug;

8. Women must not be breastfeeding;

9. Males that must agree to follow instructions for methods of contraception (see study protocol) for the duration of treatment with study drug, and then for a total of 6 months post treatment completion. In addition, male patients must not donate sperm for the time period specified above;

10. Willing and able to comply with clinic visits and study-related procedures;

11. Willing and able to provide informed consent signed by study patient or legally acceptable representative;

12. Able to understand and complete study-related questionnaires.

Exclusion Criteria:

1. 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 5 years;
2. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor;
3. Administration of a live vaccine within 30 days of the first dose of study treatment;
4. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs);
5. Diagnosis of immunodeficiency or systemic steroid therapy (i.e., dosing exceeding 10 mg of prednisone or equivalent). In case of mitotane treatment, a maximum steroid supplementation of 75 mg of cortone acetate (or equivalent hydrocortisone dose) will be accepted;
6. Uncontrolled HIV, Hepatitis B or Hepatitis C (see protocol for details);
7. History of (non-infectious) pneumonitis that required steroids or current pneumonitis;
8. Active infection requiring systemic therapy;
9. Significant cardiovascular disease, such as: history of myocardial infarction, acute coronary syndrome or coronary angioplasty / stenting / bypass grafting within the last 6 months OR CHF NYHA Class II-IV or history of CHF NYHA Class III or IV;
10. Pregnancy or breastfeeding;
11. Continued sexual activity in women of childbearing potential (physiologically capable of becoming pregnant) or sexually active men who are unwilling to practice highly effective contraception (including at least one highly effective contraception method, see study protocol) prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose;
12. History of active tuberculosis (TB, Bacillus Tuberculosis);
13. Untreated brain metastasis that may be considered active.
14. Known hypersensitivity or allergy to any of the excipients in the cemiplimab drug product.
15. Patients with a history of solid organ transplant (exception: corneal transplant)
16. Prior allogeneic stem cell transplantation, or autologous stem cell transplantation.
17. ECOG PS ≥ 2