Study of Tremelimumab and Durvalumab (MEDI4736) (T300+D) in Advanced Hepatocellular Carcinomas With Child-Pugh-B Cirrhosis

Inclusion Criteria:

1. Patients diagnosed with HCC based on pathologic diagnosis from biopsy orradiographic diagnosis on CT liver or MRI liver (i.e., Barcelona Clinic Liver Cancer (BCLC) stage B and not candidate for locoregional therapies or BCLC stage C)10

2. Patients with Child-Pugh-B7 or -B8 liver cirrhosis11

3. ECOG performance status score 0-1

4. Patients with Hepatitis B Virus (HBV) infection are required to receive effectiveantiviral therapy and have a viral load less than 500 IU/mL at screening; antiviraltherapy is not required for patients with Hepatitis C Virus (HCV) infection.

5. Adequate organ and bone marrow function:

6. Absolute neutrophil counts ≥1000/uL

7. Platelets ≥60 × 100/uL

8. Hemoglobin ≥8.0 g/dL

9. ALT and AST ≤5× upper limit of normal each

10. Bilirubin ≤3 mg/dL,

11. International normalized ratio (INR) ≤2.3 or prothrombin time ≤6 seconds abovecontrol)

12. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinineclearance CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault

1976. or by 24-hour urine collection for determination of creatinine clearance: Males: Creatinine CL (mL/min)=Weight (kg) x (140 - Age) /72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min)=Weight (kg) x (140 - Age) x 0.85 /72 x serum creatinine (mg/dL)

6. Body weight >30 kilogram (kg)

7. Capable of giving signed informed consent which includes compliance with therequirements and restrictions listed in the informed consent form (ICF) and in thisprotocol. Written informed consent and any locally required authorization (e.g.,Health Insurance Portability and Accountability Act in the US) obtained from thepatient/legal representative prior to performing any protocol-related procedures,including screening evaluations.

8. Age >18 years at time of study entry or adult male or female (according to age ofmajority as defined as ≥18 years)

9. Patient is willing and able to comply with the protocol for the duration of thestudy including undergoing treatment and scheduled visits and examinations includingfollow up.

10. Must have a life expectancy of at least 12 weeks.

11. At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 targetlesion (TL) at baseline.

Exclusion Criteria:

1. Patients who are candidates for curative treatments

2. History of uncontrolled hepatic encephalopathy in the past 6 months; patients whoare stable on medical therapy are eligible.

3. Active substance abuse or alcohol abuse at the time of consent or enrollment, whichin the opinion of the treating physician would interfere with the safety of thepatient and/or adherence to the study protocol.

4. Participants must not have a prior or concurrent malignancy whose natural history ortreatment (in the opinion of the treating physician) has the potential to interferewith the safety or efficacy assessment of the investigational regimen.

5. Prior systemic therapy for locally advanced or metastatic HCC

6. Participation in another clinical study with an investigational product during thelast 1 month.

7. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of aninterventional study.

8. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormonereplacement therapy) is acceptable. <<amend as required based on any combinationstudies with other anticancer agents>>

9. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field ofradiation within 4 weeks of the first dose of study drug

10. Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of IP. Note: Local surgery of isolated lesions for palliative intentis acceptable.

11. History of allogenic organ transplantation

12. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions tothis criterion:

13. Patients with vitiligo or alopecia

14. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement.

15. Any chronic skin condition that does not require systemic therapy

16. Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician.

17. Patients with celiac disease controlled by diet alone.

18. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent

19. History of leptomeningeal carcinomatosis

20. History of active primary immunodeficiency

21. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab or tremelimumab. The following are exceptions to this criterion:

22. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)

23. Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> ofprednisone or its equivalent.

24. Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

25. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP andup to 90 days after the last dose of IP.

26. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 90 days after the last dose of durvalumab monotherapy or180 days afterthe last dose of durvalumab and tremelimumab combination therapy.

27. Known allergy or hypersensitivity to any of the study drugs or any of the study drugexcipients.

28. Prior randomisation or treatment in a previous durvalumab and/or tremelimumabclinical study regardless of treatment arm assignment.

29. Known allergy or hypersensitivity to IP or any excipient.

30. History of another primary malignancy except for:

31. Malignancy treated with curative intent with no known active disease ≥2 yearsbefore the first dose of study intervention and of low potential risk forrecurrence.

32. Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, orlentigo maligna that has undergone potentially curative therapy.