A Phase II Study to Evaluate the Efficacy and Safety of Pembrolizumab in Combination With Mitotane in Patients With Advanced Adrenocortical Carcinoma

Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

1. Male/female participants who are at least 18 years of age on the day of signinginformed consent with histologically confirmed diagnosis of ACC will be enrolled inthis study.

2. Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 ofthis protocol during the treatment period and an additional 180 days after the lastdose of study treatment and refrain from donating sperm during this period.

3. Female participants: A female participant is eligible to participate if she is notpregnant (see Appendix 3), not breastfeeding, and at least one of the followingconditions applies:

4. a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR

5. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 duringthe treatment period plus 180 days after the last dose of study treatment.

6. The participant (or legally acceptable representative if applicable) provideswritten informed consent for the trial.

7. Have measurable disease based on RECIST 1.1. Lesions situated in a previouslyirradiated area are considered measurable if progression has been demonstrated insuch lesions.

8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.Evaluation of ECOG is to be performed within 10 days prior to the first dose of MTtherapy.

9. Have adequate organ function as defined in the following table (Table 4). Specimensmust be collected within 10 days prior to the start of study intervention.

10. The study will accept therapy naïve patients with metastatic ACC, patients whofailed one prior line of therapy not including immunotherapy, patients who startedMT within 4 weeks for metastatic disease, and patients who developed metastaseswhile on adjuvant mitotane therapy. Patients who failed platinum-based chemotherapycombined with MT may be eligible to join the study at the discretion of the PI iftheir treatment ended > 6 months before consenting for this study or if did notachieve therapeutic MT levels during prior treatment (MT level ≥ 14 mg/L).

11. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen inthe 28 days immediately preceding initiation of study treatment

12. Criteria for known Hepatitis B and C positive subjects

Hepatitis B and C screening tests are not required unless:

• Known history of HBV or HCV infection

• As mandated by local health authority

10.1 Hepatitis B positive subjects

• Participants who are HBsAg positive are eligible if they have received HBV antiviraltherapy for at least 4 weeks and have undetectable HBV viral load prior torandomization.

• Participants should remain on anti-viral therapy throughout study intervention andfollow local guidelines for HBV anti-viral therapy post completion of studyintervention.

10.2 Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening.

Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization.

Table 4 Adequate Organ Function Laboratory Values System Laboratory Value

• Hematological

• Absolute neutrophil count (ANC) ≥1500/µL

• Platelets ≥100 000/µL

• Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

• Renal

• Creatinine OR Measured or calculated b creatinine clearance (GFR can also be used inplace of creatinine or CrCl) ≤1.5 × ULN OR

≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN

• Hepatic

• Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with totalbilirubin levels >1.5 × ULN

• AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with livermetastases) Coagulation

• International normalized ratio (INR) OR prothrombin time (PT)

• Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant isreceiving anticoagulant therapy as long as PT or aPTT is within therapeutic range ofintended use of anticoagulants

• ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);

• AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase);

• GFR=glomerular filtration rate; ULN=upper limit of normal.

a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.

b Creatinine clearance (CrCl) should be calculated per institutional standard.

Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

1. A WOCBP who has a positive urine pregnancy test within 72 hours prior topembrolizumab treatment (see Appendix 3). If the urine test is positive or cannot beconfirmed as negative, a serum pregnancy test will be required.

2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent orwith an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg,CTLA-4, OX 40, CD137).

3. Has received prior systemic anti-cancer therapy including investigational agentswithin 4 weeks

4. Has received prior radiotherapy within 2 weeks of start of study intervention.Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout ispermitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

5. Has received a live vaccine or live-attenuated vaccine within 30 days before thefirst dose of study intervention. Administration of killed vaccines is allowed.

6. Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study intervention.

7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent at the time of screening)or any other form of immunosuppressive therapy within 7 days prior to the first doseof study drug. Higher dose of steroid may be permitted as replacement doses while onmitotane therapy to follow acceptable standards of care while on mitotane Knownadditional malignancy that is progressing or has required active treatment withinthe past 2 years. Note: Participants with basal cell carcinoma of the skin, squamouscell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of thebladder, that have undergone potentially curative therapy are not excluded.

8. Has known active CNS metastases and/or carcinomatous meningitis. Participants withpreviously treated brain metastases may participate provided they are radiologicallystable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening),clinically stable and without requirement of steroid treatment for at least 14 daysprior to first dose of study intervention.

9. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of itsexcipients.

10. Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment and is allowed.

11. Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

12. Has an active infection requiring systemic therapy.

13. Has a known history of Human Immunodeficiency Virus (HIV) infection

14. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA)and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA)infection. Note: Hepatitis B and C screening tests are not required unless:

• Known history of HBV and HCV infection

• As mandated by local health authority

15. Has a history or current evidence of any condition, therapy, or laboratoryabnormality or other circumstance that might confound the results of the study,interfere with the participant's participation for the full duration of the study,such that it is not in the best interest of the participant to participate, in theopinion of the treating investigator.

16. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

17. Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment.

18. Has had an allogenic tissue/solid organ transplant.