Safety and Efficacy of Intra-Arterial and Intra-Tumoral Ad-p53 With Capecitabine (Xeloda) or Anti-PD-1 in Liver Metastases of Solid Tumors and Recurrent Head and Neck Squamous Cell Cancer

Inclusion Criteria

• Signed informed consent
• Male or female, age 18 or above, who agree to use barrier contraception throughout the study. Females of child-bearing potential must be non-pregnant and non-lactating throughout the study.
• Histologically or cytologically confirmed solid tumors or hepatocellular carcinoma with known disease progression.
• Each patient entered on the study must have disease that is evaluable for response using RECIST 1.1 criteria with a minimum size of 1 cm by CT/MRI or physical examination
• Carcinoma patients in Arm A or Arm B must have received at least 1 prior regimen of standard of care systemic antitumor therapy for their metastatic disease and experienced tumor progression within 3 months after the last prior administration of the therapy or experienced unacceptable toxicity to these treatments.
• Subjects in Arm A and Arm B should have measurable CT evidence of liver metastases or liver lesions that are not treatable by surgical resection or local ablation in consultation with hepatobiliary specialist.
• The maximum tumor diameters for each Cohort for both Arm A and Arm B should achieve a dose of approximately 1x1011 viral particles (vp)/cm3 of tumor volume. (see Table 1). Please refer to Table for calculating tumor volume.
• ECOG Performance Status 0 - 1
• Either no brain metastases or irradiated stable brain metastases
• Life expectancy at least 3 months
• No prior autologous or allogeneic organ or tissue transplantation
• PT/international normalized ratio (INR) ≤ULN; aPTT ≤ULN.
• ANC ≥1500 cells/mm3
• Platelet count ≥100,000 cells/mm3
• Hemoglobin ≥9.0 g/dL
• Creatinine <2.0 mg/dL or creatinine clearance ≥50 mL/min
• Total bilirubin <1.5 x ULN
• AST and ALT <3.0 x ULN
• Alkaline phosphatase ≤5 x ULN
• Negative pregnancy test in women of childbearing potential
• Fertile patients must use effective contraception
• No non-approved investigational agents or procedures ≤4 weeks of study entry
• Patients with PRIMARY HEPATIC CANCER must have an undetectable viral load for Hepatitis B and C.
• Patients with Primary Hepatic Cancer have not recently been treated with antivirals.
• Troponin blood level within normal limits.
• Favorable biomarker profile defined by either wild type p53 gene sequence or less than 20% p53 positive tumor cells by immunohistochemistry
• Echocardiogram with normal ejection fractions
• Normal lung oxygen saturation by pulse oximeter, as determined by the Principal Investigator based on patient history and status.
• Arm C patients must have loco-regional recurrent head and neck squamous cell carcinoma (HNSCC), excluding endolaryngeal recurrence, meeting the following criteria:
• Tumor progression within 6 months of platinum-based chemotherapy
• All HNSCC lesions should be in the head and neck region and suitable for intra-tumoral injection
• The total sum of Ad-p53 Injection Doses (mL) based upon the tumor volumes shown in Table 2 should be less than or equal to 25 mL as the MTD of Ad-p53 is 2.5 x1013 vp/treatment day.

Exclusion Criteria

• Subjects must not be candidates for hepatic surgery or locoregional therapy of liver tumors with curative intent.
• Liver tumors must not be estimated to invade approximately more than one-third of the liver.
• Liver tumor-directed therapy, hepatic surgery, antibody-based therapy, or immunotherapy must not have been performed < 28 days, chemotherapy < 21 days, and targeted small molecule therapy or hormonal therapy < 14 days prior to enrollment. No radiation to tumor sites during the last 4 weeks.
• No macroscopic intra-vascular invasion by tumors of the main portal vein, hepatic vein or vena cava.
• Chronic liver dysfunction prior to development of liver metastases (Child-Pugh C or greater).
• Active alcohol dependence
• Prior radiation performed to areas of measurable disease ≤ four weeks of study entry unless there is documented evidence of disease progression.
• Use of systemic anti-cancer therapy ≤ 4 weeks, or six weeks if the systemic therapy contains a nitrosourea or mitomycin C.
• Neuropathy (≥grade 2 CTCAE)
• History of allergic reactions to any components of the treatments
• Prior additional malignancy within 2 years except for non-melanoma skin cancer, carcinoma in situ of the breast, oral cavity or cervix.
• Severe, active comorbidity, including any of the following:
• Active clinically serious infection requiring intravenous antibiotics at the time of study entry (CTCAE Grade 2)
• Hepatic insufficiency not due to tumor resulting in clinical jaundice or bilirubin >1.5 x ULN and/or coagulation defects
• Thrombotic or embolic event within the last 6 months including portal vein thrombosis
• Must not require concomitant treatment with anticoagulants
• QTcb >470 ms
• Bleeding or evidence or history of clinically significant bleeding diathesis or coagulopathy within the last 3 months
• Uncontrolled hypertension on anti-hypertensive medication (systolic blood pressure >150 mmHg or diastolic blood pressure >95 mmHg)
• Must not have been diagnosed with autoimmune disease or be immunosuppressed
• Patients with non-hepatocellular carcinoma must not have acute or chronic hepatitis B or hepatitis C infection
• Known significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or immunosuppressive medication including high-dose corticosteroids.
• Severe bleeding, hemoptysis, gastrointestinal hemorrhage, CNS bleeding, clinically significant hemorrhage or vaginal bleeding during the last 6 months
• Subjects must not have evidence of pneumonitis or inflammatory lung disease on CT scan and x-ray
• Chronic treatment for more than 6 months with systemic corticosteroids at doses above 10 mg prednisolone or equivalent before study entry
• Psychological, familial, sociological or geographical or other condition which in the opinion of the investigator would not permit study follow-up or other compliance with the study protocol.
• Subjects must not have tumors adjacent to vital structures such as carotid arteries.