Phase II Study of PD-1 Inhibitor Combined With Apatinib and Mitotane in the Treatment of Advanced Adrenal Cortical Carcinoma

Inclusion Criteria:

1. Histopathological diagnosis of adrenocortical carcinoma;

2. Patients with unresectable advanced adrenocortical carcinoma who have not receivedfirst-line standard treatment;

3. Age ≥18 years old, ≤70 years old;

4. No gender limit;

5. Eastern Cooperative Oncology Group (ECOG) score 0-1;

6. At least one measurable lesion according to Response Evaluation Criteria in SolidTumors (RECIST v1.1);

7. Major organ function within 28 days before treatment, meeting the followingcriteria:

• Blood routine test criteria (without blood transfusion within 14 days) :Hemoglobin (HB) ≥80g/L Absolute neutrophil count (ANC) ≥1.5×10^9/L Platelet (PLT) ≥80×10^9/L

• Biochemical tests must meet the following criteria: Total bilirubin (TBIL) ≤1.5times the upper limit of normal value (ULN) Alanine aminotransferase (ALT) andaspartate aminotransferase (AST) ≤2.5 ULN or ≤5 ULN if liver metastases arepresent Serum creatinine (Cr) ≤1.5 ULN or creatinine clearance (CCr)≥60 ml/min

• Coagulation testing requires the following criteria: International normalizedratio (INR) or prothrombin time (PT) ≤1.5 ULN Activated partial thromboplastintime (APTT) ≤1.5 ULN (if the patient is anticoagulated, as long as the PT andAPTT are within the intended therapeutic range)

• Cardiac markers and natriuretic peptide (BNP) ≤ULN;

8. Women of childbearing age should agree that they must use a contraceptive method (such as an intrauterine device, contraceptive pill, or condom) during the study andfor 120 days after the study; Patients had a negative serum or urine pregnancy testwithin 7 days before study entry and had to be non-lactating; Men should consent topatients who must use contraception during the study and for 6 months after the endof the study period;

9. Study participants provided written informed consent and were willing and able tofollow planned visits, study treatments, laboratory tests, and other experimentalprocedures.

Exclusion Criteria:

1. A history of other malignant tumors within the past 5 years or at the same time,except cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, andthyroid papillary carcinoma;

2. Known allergic reactions to other monoclonal antibodies, active ingredient ofmitotane, active ingredient of apatinib and or any excipients;

3. CNS metastases with clinical symptoms such as brain edema, requiring hormonalintervention, or progression of brain metastases;

4. Patients who received potent CYP3A4 inhibitor treatment within one week beforeenrollment or a potent CYP3A4 inducer treatment within two weeks before the firstuse of study drug;

5. Patients with hypertension not well controlled by antihypertensive drug therapyalone (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg);

6. NYHA class III-IV congestive heart failure;

7. Occurrence of arterial/venous thrombosis events within 1 year before enrollment,such as cerebrovascular accident (including transient ischemic attack, cerebralhemorrhage, cerebral infarction), myocardial infarction, unstable angina pectoris,deep vein thrombosis, and pulmonary embolism;

8. QT interval > 500 ms;

9. Prior systemic immunosuppressive therapy;

10. Prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies;

11. TKI treatment within 2 weeks before the first dose;

12. Participating in other interventional drug clinical trials within 4 weeks before thefirst dose;

13. Received an antineoplastic vaccine or a live vaccine within 4 weeks before the firstdose of study drug;

14. Major surgery or major trauma within 4 weeks before the first dose of studymedication;

15. Had a serious infection (CTCAE > 2) within 4 weeks before the first dose of studydrug, such as severe pneumonia requiring hospitalization, bacteremia, and infectiouscomplications; The presence of active pulmonary inflammation, symptoms and signs ofinfection within 2 weeks before the first dose of the study drug, or the need fortreatment with oral or intravenous antibiotics (excluding prophylactic antibiotics)on baseline chest imaging.

16. Have an active autoimmune disease, a history of autoimmune disease (e.g.,interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis,hyperthyroidism, hypothyroidism, including but not limited to these diseases andsyndromes); Autoimmune-mediated hypothyroidism treated with stable doses of thyroidreplacement hormone; Type 1 diabetes on stable doses of insulin; However, patientswith vitiligo or childhood asthma/allergies that had been cured and did not need anyintervention in adulthood were excluded.

17. Have a history of immunodeficiency, including being HIV positive or having otheracquired or congenital immunodeficiency disorders, or having a history of organ orbone marrow transplantation;

18. A history of non-infectious pneumonia;

19. Active pulmonary tuberculosis infection detected by medical history or CTexamination, or a history of active pulmonary tuberculosis infection within 1 yearbefore enrollment or patients who had a history of active pulmonary tuberculosisinfection 1 year ago but had not received formal treatment;

20. Subjects with active hepatitis (HBV DNA≥2000 IU/ml or 10000 copies/ml), hepatitis C (hepatitis C antibody positive and HCV-RNA above the detection limit of the assay);

21. A known history of psychotropic drug abuse, alcohol abuse, and drug use;

22. Have GI bleeding symptoms and risk of bleeding;

23. Are pregnant or lactating;

24. Have medical history, disease, treatment, or laboratory abnormalities that mayinterfere with the results of the trial or prevent the subject from participatingfully in the study, or the investigator believes that participation in the study isnot in the subject's best interest.