Gene Therapy in Treating Patients With Colon Cancer That Has Spread to the Liver

A Phase I, Open-Label, Dose-Escalating Study Of The Safety, Tolerability, And Anti-Tumor Activity Of A Single Intrahepatic Arterial Injection Of Genetically Engineered Herpes Simplex Virus, NV1020, In Subjects With Adenocarcinoma Of The Colon With Metastasis To The Liver

RATIONALE: Gene therapy may make the body build an immune response to kill tumor cells.

PURPOSE: Phase I trial to study the safety of NV1020 in patients who have colon cancer that has spread to the liver and has not responded to previous chemotherapy.

OBJECTIVES:

• Determine the safety and maximum tolerated dose of a single intrahepatic NV1020 injection in patients with hepatic metastases from colon cancer that has failed first-line chemotherapy.
• Determine the tolerability of this drug in these patients.
• Determine preliminarily the anti-tumor activity of this drug in these patients.
• Assess the immunogenicity of NV1020 in these patients.

OUTLINE: This is a dose escalation study.

Patients receive a single intrahepatic arterial injection of NV1020 over 10 minutes with the aid of hepatic arteriography.

Cohorts of 3 patients receive escalating doses of NV1020 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 patients experience dose-limiting toxicity.

Patients are followed at 1, 2, and 3 months post injection. Patients may participate in a separate long term (up to 1 year) follow-up study for continued assessment and monitoring.

PROJECTED ACCRUAL: A total of 27 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon

  • At least 3 metastatic hepatic lesions involving both lobes
  • No extrahepatic disease

• Failed first-line combination chemotherapy of fluorouracil plus either leucovorin calcium or irinotecan

• Herpes simplex virus type-1 seropositive

• Candidate for intrahepatic arterial infusion pump placement

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 70-100%

Life expectancy:

• Not specified

Hematopoietic:

• WBC greater than 3,000/mm^3
• Absolute neutrophil count greater than 1,500/mm^3
• Platelet count greater than 100,000/mm^3
• Hemoglobin greater than 9.0 g/dL
• No history of any blood clotting disorder (e.g., hemophilia)

Hepatic:

• Transaminases no greater than 3 times upper limit of normal
• Bilirubin no greater than 2.0 mg/dL
• No active hepatitis
• No history of hepatic fibrosis, cirrhosis, or hemochromatosis

Renal:

• Creatinine no greater than 2.0 mg/dL

Other:

• Not pregnant or nursing
• Negative pregnancy test
• All patients must use effective barrier contraception during and for at least 6 months after study
• HIV negative
• No active herpes infection
• No other active uncontrolled infection
• No prior weight loss of more than 10 lbs within the past month
• No history of alcohol or other substance abuse
• No concurrent unstable and/or severe medical or psychological condition
• No history of any other medical or psychological condition that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 4 weeks since prior immunotherapy (e.g., interleukin-2, interleukin -12, or interferon)
• No prior gene transfer therapy
• No prior therapy with cytolytic virus of any type
• No concurrent immunotherapy during and for 28 days after study therapy
• No concurrent vaccines during and for 28 days after study therapy

Chemotherapy:

• See Disease Characteristics
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• No concurrent chemotherapy during and for 28 days after study therapy

Endocrine therapy:

• No concurrent systemic steroids during and for 28 days after study therapy

Radiotherapy:

• No prior radiotherapy to the liver
• No concurrent radiotherapy during and for 28 days after study therapy

Surgery:

• At least 2 weeks since prior surgery

Other:

• At least 30 days since prior participation in investigational study
• No concurrent antiviral agent active against herpes simplex virus (e.g., acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscarnet, or cidofovir) during and for 28 days after study therapy
• No concurrent immunosuppressive agents (e.g., cyclosporine) during and for 28 days after study therapy
• No other concurrent investigational or anti-cancer agents during and for 28 days after study therapy