Interferon-Beta Gene Transfer (Ad.hIFN-β) as Treatment for Refractory Colorectal Carcinoma With Liver Metastases

• Evaluate the MTD or maximum feasible dose (MFD) of Ad.hIFN-β.
• Evaluate IFN-β and Ad.hIFN-β vector serum concentrations.
• Evaluate immunogenicity of Ad.hIFN-β by measuring human anti adenovirus and human anti-IFN-β antibody formation.
• Explore preliminary clinical activity.

• - Evaluate the MTD or maximum feasible dose (MFD) of Ad.hIFN-β.
• - Evaluate IFN-β and Ad.hIFN-β vector serum concentrations.
• - Evaluate immunogenicity of Ad.hIFN-β by measuring human anti adenovirus and human anti–IFN-β antibody formation.
• - Explore preliminary clinical activity.

This study will be conducted in subjects with refractory colorectal carcinoma with unresectable liver metastases. The purposes of the study are:

• to evaluate the safety and any harmful effects of an intravenous injection of Ad.hIFN-β;
• help determine whether the virus carrying the interferon-beta gene will enter the bloodstream and liver tumor cells and cause the cancer cells to die.

This trial is a clinical research study of Ad.hIFN-β, an investigational, replication-defective, recombinant adenovirus containing the human interferon beta gene, for people that have refractory colorectal carcinoma with liver metastases. Scientists have been exploring a variety of approaches to develop medications to treat patients with refractory colorectal carcinoma with liver metastases; a disease for which current treatment provides only limited relief, so there is a need for new medications.

• Colorectal Carcinoma
• Metastases

Inclusion Criteria:

• Subjects with histologically confirmed hepatic metastases from primary colorectal carcinoma.
• Not amenable to complete surgical resection for attempted cure as determined by the Principal Investigator (PI).
• Tumor progression after prior therapy for colorectal carcinoma, including fluoropyrimidine (5 FU or capecitabine), irinotecan, oxaliplatin, or cetuximab.
• One or more metastatic hepatic tumors that is measurable on CT scan. In addition, subjects may have nonhepatic metastatic tumors.
• ECOG performance status of ≤ 1.
• Age ≥ 18 years.
• Signed, written IRB-approved informed consent.
• Men and women of reproductive potential must be willing to follow accepted birth control methods during treatment and for 3 months after completion of treatment.

• Acceptable liver function:

  • Bilirubin ≤ 1.5 x upper limit of normal;
  • AST, ALT ≤ 2.0 x upper limit of normal;
  • Albumin ≤ 3.0 g/dL.

• Acceptable hematologic status:

  • Granulocyte ≥ 1000 cells/mm3;
  • Platelet count ≥ 150,000 plts/mm3;
  • Hemoglobin > 9 g/dL.
• Acceptable coagulation status: INR within normal limits.
• Acceptable kidney function: Serum creatinine within normal limits.

Exclusion Criteria:

• New York Heart Association Class III or IV cardiac disease, myocardial infarction within the past 6 months prior to Day 1, unstable arrhythmia, or evidence of ischemia on ECG within 14 days prior to Day 1.
• Seizure disorders requiring anticonvulsant therapy.
• Severe chronic obstructive pulmonary disease with hypoxemia.
• Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1.
• Active uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.
• Pregnant or nursing women.
• Treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within 1 month prior to study entry.
• Unwillingness or inability to comply with procedures required in this protocol.
• Known infection with HIV, hepatitis B, or hepatitis C.
• Serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the investigator and/or the sponsor.
• Clinically significant bleeding event within the last 3 months, unrelated to trauma.
• More than 50% of liver replaced by tumor (estimated by the PI from CT scan within 14 days of Day 1).
• Previous treatment with Ad.hIFN-β.
• Any prior treatment with a gene delivery vector or an adenovirus therapeutic agent.