Phase I Study of RNA Oligonucleotide, MTL-CEBPA, Atezolizumab and Bevacizumab in Patients With Advanced Hepatocellular Carcinoma.

Exclusion Criteria

• •* Child-Pugh class B or C
• •* Patients who have been treated with loco-regional therapy within the last 28 days prior to study treatment initiation
• •* Major surgery within the last 28 days prior to study treatment initiation
• •* Any systemic therapy or investigational agent in the advanced setting within 28 days prior to initiation of study treatment
• •* Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies or treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 \[IL-2\]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment.
• •* Grade \> 1 prior treatment-related toxicity (excluding alopecia) at the time of screening
• •* Use of filgrastim or peg-filgrastim 14 days prior to study entry
• •* Patients with clinically significant cancer ascites
• •* Any episode of bleeding from oesophageal varices or other uncontrolled bleeding within the last 6 months prior to study treatment initiation
• •* Patients administered with serum albumin within the last 7 days prior to the first study drug administration
• •* Known infection with human immunodeficiency virus (HIV)
• •* Known active tuberculosis (TB)
• •* Leptomeningeal metastasis
• •* Symptomatic brain metastases. Asymptomatic patients with treated brain metastases are eligible, provided that all of the following criteria are met:
• •1. Measurable disease, per RECIST v1.1, must be present outside the CNS.
• •2. The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.
• •3. There is no evidence of interim progression between completion of CNS-directed therapy and initiation of study treatment.
• •4. The patient has not undergone stereotactic, whole-brain radiotherapy, and/or neurosurgical resection within 28 days prior to initiation of study treatment.
• •5. Are not receiving corticosteroids or corticosteroids in doses no greater than physiological replacement (e.g., dexamethasone \< 1.5 mg/day). Anticonvulsant therapy at a stable dose is permitted.
• •6. Asymptomatic patients with brain metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan.
• •* Treatment with strong CYP3A4 inducers within 14 days prior to initiation of study treatment, including rifampin (and its analogues) or St. John's wort.
• •* Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:
• •Patients who received acute, low-dose (≤10 mg prednisolone or equivalent per day), systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy, premedication to prevent infusion reaction) are eligible for the study after PI approval has been obtained. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
• •Inadequately controlled arterial hypertension (defined as systolic blood pressure (BP) ≥150 mmHg and/or diastolic blood pressure ≥100 mmHg. Anti-hypertensive therapy to achieve these parameters is allowed.
• •Prior history of hypertensive crisis or hypertensive encephalopathy
• •Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment
• •History of significant hemoptysis (≥2.5 mL of bright red blood per episode) within 1 month prior to initiation of study treatment
• •Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
• •Patients on anticoagulation for therapeutic purposes and is unable to discontinue anti-coagulation (see section 4.12.3 for prohibited anti-coagulant drugs)
• •Patients on warfarin (for therapeutic or prophylactic purpose)
• •History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, bowel obstruction or intra-abdominal abscess within 6 months prior to initiation of study treatment.
• •Clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of study treatment. Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction at time of initial diagnosis may be enrolled if they had received definitive (surgical) treatment for symptom resolution.
• •Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture.
• •Radiotherapy within 28 days prior to initiation of study treatment, except palliative radiotherapy to bone lesions within 7 days prior to initiation of study treatment.
• •Local therapy to liver (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization, etc.) within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure.
• •Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
• •1. Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
• •2. Patients with vitiligo or alopecia
• •3. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• •4. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided that they do not require systemic therapy
• •5. Patients with celiac disease controlled by diet alone.
• •History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• •History of congenital long QT syndrome or corrected QT interval \> and = 500 ms (calculated with use of the Fridericia method) at screening.
• •Signs and symptoms of heart failure characterised as greater than the New York Heart Association (NYHA) Class I or other clinically significant cardiac abnormalities (including history of myocardial infarction) including stable abnormalities.
• •Patients with history of stem cell / solid organ transplantation.
• •Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
• •Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
• •Pregnant or lactating women
• •Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab.
• •Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
• •Any other condition (e.g., known or suspected poor compliance, etc.) that, in the judgment of the investigator, may affect the participant's ability to follow the protocol specific procedures.
• •Known hypersensitivity to Chinese hamster ovary cell products or the active substance (MTL-CEBPA, atezolizumab or bevacizumab).
• •History of malignancy other than HCC within 5 years prior to screening, with the exception of adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
• •Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high risk for bleeding.
• •A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment.