聚肌苷酸-聚胞苷酸-聚-L-賴氨酸羧甲基纖維素（poly-ICLC）是一種合成的雙鏈核糖核酸，可作為病原體相關分子模式的病毒模擬物。 Poly-ICLC可被兩種不同的受體識別，即Toll-like rectpor-3（TLR3）和胞質黑素瘤分化相關基因5（MDA5），並進一步誘導及激活許多免疫細胞。根據動物實驗及其他早期臨床試驗，腫瘤內注射poly-ICLC可導致細胞死亡並釋放更多的腫瘤相關抗原。靜脈或肌肉注射poly-ICLC則可作為較佳的疫苗佐劑，引發並擴增CD8 T細胞，並且誘導T細胞浸潤到腫瘤內部。因此，我們假設poly-ICLC可以促進抗PD1抗體治療肝癌的效果。在這項臨床試驗中，我們將依序在腫瘤內及肌肉內注射poly-ICLC並且合併保疾伏治療，並進一步評估上述治療方式在無法切除的肝癌患者身上的安全性和治療效果。

評估poly-ICLC 及保疾伏合併使用在無法開刀的肝癌患者的安全性與療效

Hiltonol®

Polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose(POLY-ICLC)

注射液劑

1.8mg/ml

Primary efficacy assessment
1. To evaluate the safety of intratumoral (IT) and intramuscular (IM) Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (Poly-ICLC, Hiltonol) in combination with Nivolumab for the treatment of patients with unresectable hepatocellular carcinoma.

Secondary efficacy assessment
1. To evaluate overall response rate (ORR) as assessed by the mRECIST (modified Response Evaluation Criteria in Solid Tumors) as recorded on imaging at 12 and 24 weeks time points compared to baseline.
2. To determine progression free survival (PFS) and overall survival (OS) rate at 6, 12 and 24 months.
3. To determine whether the study regimen of Poly-ICLC plus Nivolumab will induce T cell immune responses in the peripheral blood and in the tumors.
4. To determine the durability of the therapeutic effect.

納入條件:
1. Histologically confirmed diagnosis of hepatocellular carcinoma.
2. Must be 20 years of age or older.
3. Unresectable disease. Patients with resectable HCC but who refuse surgery may be enrolled after a documented consultation with a surgeon.
4. Radiologically measurable disease that is at least 2 cm in longest dimension of the target tumor.
5. ECOG performance status of ≤ 2.
6. Child-Pugh classification A.
7. Patients with chronic hepatitis B must be under long-term anti-viral agents with a high barrier of resistance, such as Entecavir, Tenofovir Disoproxil Fumarate, or Tenofovir Alafenamide.
8. Patients with chronic hepatitis C must reach sustained viral response by the treatment with any direct acting agent.
9. Acceptable hematologic, renal and liver function as follows within 28 days before entering the trial:
(A) Absolute neutrophil count ≥ 1500/mm3
(B) Platelets ≥ 80,000/mm3
(C) Hemoglobin > 10.0 g/dL
(D) Creatinine ≤ 2.0 mg/dl
(E) Total bilirubin ≤ 1.5 mg/dl, unless due to Gilbert’s syndrome
(F) Transaminases (AST and ALT) ≤ 2 times above the upper limits
(G) INR < 1.5
10. Patients must be able to provide informed consent.
11. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
12. Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Contraception must be continued for at least 5 months following the last dose of Nivolumab. Women of childbearing potential must have a negative pregnancy test. Women who have been menopausal for more than 1 year (more than 12 months since their last menstrual period) or patients who have undergone sterilization are not required to undergo pregnancy testing.

排除條件:
1. Patients may not be receiving any other investigational agents, biological agents or other anti-cancer medication.
2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring antibiotics (exception is a brief (≤10days) course of antibiotics to be completed before initiation of treatment), symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements.
3. Based on its mechanism of action and data from animal studies, Nivolumab can cause fetal harm when administered to a pregnant woman. Patients must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
4. Has a diagnosis of primary immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Patients on chronic steroids (more than 4 weeks at stable dose) equivalent to ≤ 10mg prednisone will not be excluded.
5. Has active autoimmune disease that has required systemic treatment in the past 1 year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is acceptable.
6. HIV positive with detectable viral load, or anyone not on stable anti-viral (HAART) regimen, or with <200 CD4+ T cells/microliter in the peripheral blood.
7. History of allogeneic hematopoietic cell transplantation or solid organ transplantation.
8. Documented allergic or hypersensitivity response to any protein therapeutics (e.g., recombinant proteins, vaccines, intravenous immune globulins, monoclonal antibodies, receptor traps)
9. The target tumor is blocked by the bile duct or important blood vessel that leads to difficulty in intratumor injection.
10. Principal investigator believes that for one or multiple reasons the patient will be unable to comply with all study visits, or if they believe the trial is not clinically in the best interest of the patient.

-