Patient case: 72-year-old male with melanoma; genetic feature: TP53 loss of function

Clinical trial: Safety and Efficacy of Intra-Arterial Ad-p53 in Liver Metastases of Solid Tumors

Summary: This is a Phase 1 study of the combination of Ad-p53 administered intra-arterially in combination with oral metronomic capecitabine in patients with unresectable, refractory liver metastases of colorectal carcinoma (CRC) and other solid tumors, including primary hepatocellular carcinoma (HCC). This safety study has a standard 3+3 design. The Maximum Tolerated Dose (MTD) will be determined as well as the general safety and preliminary efficacy using RECIST 1.1 and Immune-Related Response Criteria. CEA levels will also be followed.

Detailed description: This is a Phase 1 study of the combination of Ad-p53 administered intra-arterially in combination with oral metronomic capecitabine in patients with unresectable, refractory liver metastases of colorectal carcinoma (CRC) and other solid tumors, including primary hepatocellular carcinoma (HCC). This safety study has a standard 3+3 design, with dosing following the initial cohort determined by MTD and DLT criteria as well as safety and tolerance. Patients will be followed for adverse events and preliminary efficacy. The Maximum Tolerated dose (MTD) will be determined as well as the general safety and preliminary efficacy using RECIST 1.1 and Immune-Related Response Criteria. CEA levels will also be followed. Biomarker testing of archival or fresh tissue is performed during the study. Patients will undergo a maximum of 2 8-week cycles, with scans every 8 weeks. No additional biopsies are planned following Screening. Enrollment will be up to 24 patients.

Eligibility: Inclusion Criteria:
  1. Signed informed consent
  2. Male or female
  3. Histologically or cytologically confirmed solid tumors or hepatocellular carcinoma with known disease progression.
  4. Subjects 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.
  5. Age ≥18
  6. ECOG Performance Status 0 - 1
  7. Either no brain metastases or irradiated stable brain metastases.
  8. Life expectancy ≥ 5 months
  9. No prior autologous or allogeneic organ or tissue transplantation
  10. PT/international normalized ratio(INR) ≤ ULN; aPTT ≤ ULN
  11. New York Heart Association classification <III
  12. ANC ≥ 1500 cells/mm3
  13. Platelet count ≥100,000 cells/mm3
  14. Hemoglobin ≥10.0 g/dL
  15. Creatinine < 2.0 mg/dL or creatinine clearance ≥ 60 mL/min
  16. Total bilirubin < 1.5 x ULN
  17. AST and ALT < 3.0 x ULN
  18. Negative pregnancy test in women of childbearing potential
  19. Fertile patients must use effective contraception
  20. No non-approved investigational agents or procedures £4 weeks of study entry
  21. Favorable tumor p53 biomarker profiles for Ad-p53 efficacy defined by either wild-type p53 gene configuration or £20% p53 positive cells by immunohistochemistry
  22. Child-Pugh score must be A to B7
  23. Patients with HCC must have an undetectable viral load for Hepatitis B and C.
  24. Patients with HCC must not recently have been treated with antivirals.
  Exclusion Criteria:
  1. Subjects must not be candidates for hepatic surgery or locoregional therapy of liver tumors with curative intent.
  2. Liver tumors must not be estimated to invade approximately more than one-third of the liver.
  3. 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. Nor radiation to tumor sites during the last 4 weeks.
  4. No macroscopic intra-vascular invasion by tumors of the main portal vein, hepatic vein or vena cava.
  5. Chronic liver dysfunction prior to development of liver metastases (Child-Pugh C or greater)
  6. Active alcohol dependence
  7. Neuropathy ( ≥ grade 2 NCI-CTC)
  8. History of allergic reactions to any components of the treatments
  9. Prior malignancy within 2 years except for non-melanoma skin cancer, carcinoma in situ of the breast, oral cavity or cervix.
  10. Severe, active comorbidity
  -  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 human immunodeficiency virus (HIV)
  -  Severe bleeding, hemoptysis, gastrointestinal hemorrhage, CNS bleeding
  -  Clinically significant hemorrhage or vaginal bleeding during the last 6 months
  11. Chronic treatment for more than 6 months with systemic corticosteroids at doses above 10 mg (prednisolone or equivalent) before study entry
  12. 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.

Relevance to patient case: possibly relevant