Alectinib in Combination with Nivolumab in the Treatment of Recurrent or Refractory HCC Patients Guided with Serum RNase1 and Tumor Expression of PD-L1

Inclusion Criteria:

1. Age ≥20 years, at time of signing Informed Consent Form.

2. Histologically confirmed hepatocellular carcinoma, and the HCC cells harbor onlywild-typed ALK.

3. Who has failed local treatments and at least one line of standard TKI treatment (sorafenib or lenvatinib) and not eligible for immune check point inhibitortreatment.

4. Life expectancy ≥ 12 weeks

5. At least one measurable (per RECIST 1.1) lesion. Patients who received prior localtherapy (e.g., radiofrequency ablation or transarterial chemoembolization, etc.) areeligible provided the target lesion(s) have not been previously treated with localtherapy or the target lesion(s) within the field of local therapy have subsequentlyprogressed in accordance with RECIST version 1.1.

6. ECOG Performance Status of 0 or 1 within 7 days prior to registration

7. Child-Pugh class A (see Appendix) or B7-8 within 14 days prior to registration

8. Adequate hematologic and end-organ function, defined by the following laboratorytest results, obtained within 7 days prior to registration, unless otherwisespecified:

9. ANC ≥ 1.5 109/L(1500/μL) without granulocyte colony-stimulating factorsupport; platelet count ≥ 75109/L(75000/μL) without transfusion; andhemoglobin≥ 90 g/L (9 g/dL)(patients may be transfused to meet this criterion).

10. Liver transaminases (AST and ALT) ≤ 5 *upper limit of normal (ULN)

11. Serum creatinine ≤ 1.5 * ULN or creatinine clearance≥ 50 mL/min (calculatedusing the Cockcroft-Gault formula)

12. Urine dipstick for proteinuria ≤ 2+ (within 7 days prior to initiation of studytreatment). Patients who have ≥ 2+ proteinuria on dipstick urinalysis atbaseline will be eligible if he/she have daily protein excretion of ≤ 1gdocumented by a 24-hour urine collection.

13. Women of childbearing potential must agree to use contraceptive methods with afailure rate of < 1% per year (e.g., hormonal contraceptives that inhibit ovulation,copper intrauterine devices) during the treatment period and for at least 6 monthsafter the last dose of Alectinib (Alecensa) in Combination with Nivolumab (Opdivo).

14. Men must agree to use contraceptive measures (condom plus an additionalcontraceptive method that together result in a failure rate of < 1% per year) duringthe treatment period and for 6 months after the last dose of Alectinib (Alecensa) inCombination with Nivolumab (Opdivo).

Exclusion Criteria:

1. Intolerant or severe allergic reactions to Alectinib (Alecensa) or Nivolumab (Opdivo)

2. Symptomatic central nervous system metastases. Brain metastases that have previouslybeen treated and are stable for 4 weeks before the first dose date are allowed.

3. Prior treatment with Alectinib (Alecensa) and/or Nivolumab (Opdivo), or priortherapy with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody (or any otherantibody or drug specifically targeting T-cell costimulation or checkpoint pathways)for any reason.

4. Locoregional HCC therapy (e.g., TACE, RFA), systemic chemotherapy, hormonal therapy (e.g., tamoxifen) or investigational therapy within 4 weeks (or 5 half-lives,whichever is shorter) prior to Screening.

5. Life expectancy of less than 12 weeks

6. Major surgery or significant trauma within 14 days prior to Screening. Minor surgerywithin 7 days prior to Screening (excluding the placement of central/peripherallines or skin biopsy).

7. Not recovered from the acute toxic effects of prior anticancer therapy, radiation ormajor surgery/significant trauma at Screening.

8. Major systemic diseases that the investigator considers inappropriate forparticipation

9. Known human immunodeficiency virus (HIV) infection

10. Concurrent active second malignancy for which the subject is receiving therapy,excluding non-melanomatous skin cancer, non-progressive prostate cancer treated withhormonal therapy, or carcinoma in situ of the cervix. Any cancer curatively treated >5 years prior to entry is permitted.

11. Uncontrolled intercurrent illness including, but not limited to ongoing or activeinfection (e.g., tuberculosis) requiring antibiotic, antifungal, or antiviraltherapy (other than antiHBV therapy), symptomatic heart failure, cardiac arrhythmia,acute or chronic pancreatitis or psychiatric illness/social situations that wouldlimit compliance with study requirementsCNS metastasis.

12. Any active autoimmune disease or history of known autoimmune disease except forvitiligo, resolved childhood asthma/atopy, type I diabetes mellitus, residualhypothyroidism due to autoimmune condition only requiring hormone replacement,psoriasis not requiring systemic treatment, or conditions not expected to recur inthe absence of an external trigger are permitted to enroll.

13. Ongoing other concurrent investigational agents or anticancer therapy

14. Radiotherapy within 28 days prior to initiation of study treatment, except forpalliative radiotherapy to bone lesions. Symptomatic lesions (e.g., bone metastasesor metastases causing nerve impingement) amenable to palliative radiotherapy shouldbe treated prior to enrollment. Patients should be recovered from the effects ofradiation. There is no required minimum recovery period.

15. Presence of central nervous system (CNS) or leptomeningeal metastases. Patients witha history of CNS metastases are eligible for the study if he/she have receivedradiotherapy or surgery for the CNS metastases, and complete response (no evidenceof residual CNS metastases) must be documented by brain CT scan at screening.

16. Requirement of systemic treatment with either corticosteroids (> 10 mg dailyprednisone equivalents) or other immunosuppressive medications within 14 days ofstudy drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of activeautoimmune disease.

17. Prior organ allograft or allogeneic bone marrow transplantation.

18. Other severe acute or chronic medical or psychiatric conditions, or laboratoryabnormality that may increase the risk associated with study participation and inthe judgment of the investigator would make the patient inappropriate for entry intothis study.

19. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently). Patients with indwellingcatheters (e.g., PleurX) are allowed