This is a single arm, nonrandomized, single center clinical study to investigate the safety and efficacy of regorafenib combined with PD-1 inhibitor therapy for second-line treatment of hepatocellular carcinoma

To observe and evaluate the efficacy, safety and biomarker analysis of regorafenib combined with PD-1 inhibitor for the second-line treatment of hepatocellular carcinoma.In this study, 20 patients with hepatocellular carcinoma will be enrolled for regorafenib combined with PD-1 inhibitor therapy.In the absence of any of the following conditions, such as withdrawal of informed consent by subjects, intolerable drug side effects, or the investigator's determination that further study is not appropriate, the expected study treatment for each subject will continue until radiologically confirmed tumor progression. Efficacy indicators and safety indicators will be observed during the trial.

Inclusion criteria

Subject must meet all of the following criteria to be enrolled in the study:

1. Subjects volunteer to participate in the study, agree to sign their written informed consent, show good compliance and are cooperative with the follow-up.

2. There is no gender requirement but age requirement (age>18) for the subjects who sign the informed consent.

3. The subjects were diagnosed as advanced hepatocellular carcinoma (HCC) by imaging or histological examination.

4. The disease is not suitable for radical surgery and/or local treatment, or disease progression occurs after surgery and/or local treatment.

5. The patients with at least one measurable lesion according to RECIST, version1.1, and no local radiotherapy was performed. Results of spiral CT scan (RECIST, version 1.1): LD (lesion) ≥ 10 mm or SD (enlarged lymph node) ≥ 15 mm.

6. The patients who failed or were intolerable to the following treatments: simple sorafenib therapy, or sorafenib combined with PD-1 therapy, or simple lenvatinib therapy, or lenvatinib combined with PD-1 therapy, or bevacizumab combined with atezolizumab.

7. Definition of treatment failure: It refers to the disease progression during treatment or the recurrence of the disease after treatment (Obvious disease recurrences and progressions appeared in patients who have received at least one radical or palliative resection, interventional therapy or radiotherapy. The treatment period of systemic chemotherapy like oxaliplatin and other systemic chemotherapy must be at least one cycle. The treatment time of molecular targeted therapy must be longer than 14 days).

8. Definition of intolerable: Hematological toxicity ≥ Grade IV, or non-hematological toxicity ≥ Grade III, or damage to the heart, liver, kidney and other major organs ≥ Grade II occurred during the treatment. For details, please refer to the package inserts of each drug.

9. The ECOG score within 1 week before enrollment was 0-1 points.

10. Child-Pugh score for liver function: Class A, BCLC staging is B-C stage.

11. The time from failure of first-line system treatment to enrollment in this study (the time to sign the informed consent form) was ≥ 2 weeks , and the adverse events basically returned to normal (NCI-CTCAE ≤ Grade I).

12. The expected survival time is greater than or equal to 6 months.

13. HBV DNA < 2000 IU/ml (104 copies/ml).

14. Hematology and organ function are adequate, based on the following laboratory test results obtained within 14 days prior to the start of study treatment (unless otherwise stated):

    14.1 Routine blood test: (No blood transfusion, G-CSF treatment, or medication correction within 14 days prior to screening) 14.2 Hb ≥ 100 g/L; Neutrophils ≥ 1.5 × 109/L; PLT ≥ 75 × 109/L 14.3 Biochemical examination: (No ALB was administered within 14 days) ALB ≥ 35 g/L; ALT and AST<3×ULN; TBIL ≤ 2×ULN; Creatinine ≤ 1.5×ULN; PT ≤ ULN+4S; INR ≤ 2.2 (In the Child-Pugh score, only one of albumin and bilirubin can be scored as 2 points)

15. No active autoimmune disease requiring systemic treatment in the past 2 years (i.e. using disease modulators, corticosteroids, or immunosuppressive agents). Alternative therapy (e.g., physiological corticosteroid replacement therapy for thyroxine, insulin, or adrenal or pituitary insufficiency, etc.) is not considered as a form of systemic therapy.

16. Reproductive women: Agree to abstain from sex (avoid heterosexual intercourse) or use a contraceptive method with an annual contraceptive failure rate < 1% during treatment and for at least 6 months after the last administration.

    16.1 If the female patient has menstruation and has not yet reached the post-menopausal state (continuous non-menstrual period ≥ 12 months, with no other reasons other than menopause are found), and have not undergone sterilization (removal of the ovaries and/or uterus), it is considered that the patient is fertile.

    16.2 Examples of contraceptive methods with an annual contraceptive failure rate < 1% include bilateral fallopian tube ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper-ring intrauterine devices.

    16.3 The reliability of sexual control should be evaluated relative to the duration of the clinical trial and the preferred and daily lifestyle of the patient. Periodic abstinence (for example, calendar days, ovulatory period, symptomatic body temperature, or post-ovulation methods) and external ejaculation are unacceptable methods of contraception.

17. Male: Agree to abstinence (not having heterosexual intercourse) or use contraceptive measures, and agree not to donate sperm, defined as follows:

    17.1 When his female partner has fertility, the male patient must abstain from sex during treatment and within 6 months after the last administration, or use condoms and other contraceptive methods to make the annual contraceptive failure rate < 1%. Male patients must agree not to donate sperm during the same time period. When his female partner is pregnant, the male patient must abstain from sex or use a condom for contraception during the treatment period and within 6 months after the last dose to avoid the fetus being affected by the study.

18. The reliability of sexual control should be evaluated relative to the duration of the clinical trial and the preferred and daily lifestyle of the patient. Periodic abstinence (for example, calendar days, ovulatory period, symptomatic body temperature, or post-ovulation methods) and external ejaculation are unacceptable methods of contraception.

19. Before the first dose of study medication for biomarker analysis, archived tumor tissue or new tissue biopsy specimens must be available. In the case when the archived tissue cannot be provided, and the biopsy cannot be performed, participants can consult the investigator and join the group after obtaining the investigator's consent.

Note: If an unstained section is submitted, the new section should be submitted to the testing laboratory within 14 days after cutting.

Exclusion criteria：

Patients meeting one or more of the following conditions cannot be included:

1. The clinical stage is stage IV, and/or patients with hepatobiliary solid tumors with any of the following conditions:

   1.1 The patient is suitable for surgical radical treatment, 1.2 or, the patient has accepted radical treatment and has no assessable lesion, 1.3 or, the patient has a history of liver transplantation or plans to undergo liver transplantation.

2. Patient who is known to be allergic to recombinant humanized PD-1 monoclonal antibody drugs and their components; Patient who is known to be allergic to regorafenib and its components.

3. ECOG score ≥ 2 points.

4. Patient who has ascites with clinical symptoms, that requires therapeutic abdominal puncture or drainage, or Child-Pugh score > 2 points.

5. Patient with serious heart, cerebrovascular and other systemic diseases with unstable or uncontrollable condition.

6. Patient with active central nervous system (CNS) metastasis and/or cancerous meningitis. Subjects with previously treated brain metastases can participate in the study, as long as their brain metastases are stable (imaging shows no evidence of progression for at least four weeks before the first trial treatment and all neurological symptoms have returned to baseline) with no evidence shows new or enlarged brain metastases, and steroids are not used for at least 7 days before the trial treatment. This exception does not include cancerous meningitis, which is excluded regardless of how its clinical stability is.

7. Patient who has accepted major surgery within 4 weeks before the first study administration (appropriate wound healing and clinical evaluation must be performed after major surgery, which has nothing to do with the time of enrollment)

8. Patient with liver and kidney dysfunction, such as jaundice, ascites, and/or bilirubin > 2×ULN, and/or alkaline phosphatase ≥ 3×ULN; and/or ≥ Grade 3 (CTC-AE 5.0) persistent proteinuria, creatinine ratio > 3.5g/24 hours, or renal failure requiring blood or peritoneal dialysis, etc.

9. Urine routine test shows urine protein ≥ ++ or confirmed 24-hour urine protein quantification>1.0g;

10. Patient with persistent infection which is greater than Grade 2 (CTC-AE5.0).

11. Patient with a history of organ allogeneic transplantation (participants underwent allogeneic tissue/solid organ transplantation)

12. Patient with a history of active tuberculosis (TB bacilli)

13. Patient intolerance to any study drug (or any excipient)

14. Female patient who is pregnant, breastfeeding, or who does not accept contraceptive measures.

15. Patient with known or untreated brain metastases, or with epilepsy which needs medication.

16. Patient with bone metastases who have received palliative radiotherapy (radiotherapy area > 5% bone marrow area) within 4 weeks before participating in the study, or patient who has unhealed wounds, ulcers or fractures, or has a history of organ transplantation.

17. Patient with a history of gastrointestinal bleeding or a clear gastrointestinal bleeding tendency within the past 6 months, such as: esophageal varices with bleeding risk, local active ulcer lesions and fecal occult blood ≥ (++). Gastroscopy is needed for patients with stool occult blood (+);

18. There is evidence or history of bleeding mechanism disorders such as bleeding events ≥ Grade 3 (CTC-AE5.0).

19. Patient with a history of human immunodeficiency virus (HIV) infection.

20. Patient who tests positive for hepatitis B or C and has not received regular treatment.

21. Patient with severe non-healing wounds, ulcers or fractures

22. Patient treated with regorafenib beforehand.

23. Patient diagnosed of immunodeficiency or received systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of study treatment. After consultation with the sponsor, the use of physiological doses of corticosteroids (not exceeding 7.5 mg/d prednisone or equivalent doses of similar drugs) can be approved.

24. Existence of drug abuse; or any medical, psychological or social condition that may affect the research and patient compliance, or even endanger patient safety.

25. There are many factors that affect oral medications (such as inability to swallow, chronic diarrhea, and intestinal obstruction, and conditions which significantly affect the administration and absorption of drugs).

26. There is unresolved toxicity > Grade 1 caused by any previous treatment/manipulation (CTC-AE5.0, except for hair loss, anemia, and hypothyroidism).

27. Patient who received live virus vaccine within 30 days of the planned start of treatment. Seasonal influenza vaccine without live virus is allowed.

28. Patients with objective evidence showing pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severely impaired lung function, etc. in the past and at present.

29. Patient who received strong CYP3A4 inhibitor treatment within 7 days before participating in the study, or received strong CYP3A4 inducer treatment within 12 days before participating in the study.

30. Patient who is participating in another clinical study at the same time.

31. Patient who was considered to be unsuitable to participate in this study after the investigator comprehensively judged the condition.

Termination criteria：

1. The subject withdraws the informed consent and asks to withdraw.
2. Medical imaging examination confirms the progression of disease, and the treatment is not beneficial for disease progression through clinical judgment.
3. After dose adjustment, the subject still cannot tolerate toxicity.
4. Other conditions that the investigator considers necessary for the subject to withdraw from the study.
5. The sponsor terminates the study due to security concerns.