Safety & Efficacy of NV1020 in Colorectal Cancer Metastatic to the Liver

A Phase I/II, Open-label Study to Evaluate the Safety and Anti-tumor Effects of NV1020 Administered Repeatedly Via Hepatic Artery Infusion Prior to Second-line Chemotherapy, in Patients With Colorectal Adenocarcinoma Metastatic to the Liver

This study is an open-label study. It has two stages. Stage 1 is a dose escalation phase of the study to determine and evaluate the safety and tolerability of repeated treatments with a genetically engineered herpes simplex virus NV1020 administered locoregionally to the liver.

Stage 2 is to evaluate the dose found in Stage 1 to be "optimally tolerated". Stage 2 is to assess the efficacy of the optimally tolerated dose of NV1020 by itself and in combination with second-line chemotherapy.

Assignment to Stage 1 or Stage 2 of the study is determined by when the patient enters the study.

This study is designed to evaluate the effects of repeated treatments with NV1020, prior to second-line chemotherapy, and to determine an appropriate dose level of NV1020 in a multiple dose regimen for later Phase II studies.

Sequential, open-label cohort dose escalation of NV1020 (stage 1) followed by an expansion of one selected dose cohort (stage 2).

Study results will be reviewed periodically by an independent DSMB who will approve each cohort dose escalation.

During the dose escalation stage, 3 cohorts of patients (3 in each) will be treated with 4 fixed doses of NV1020, with the dose level increasing for successive cohorts. A patient will be observed for a minimum of 7 days after the first NV1020 infusion before the next patient in the same cohort is given NV1020. The first patient in the next higher dose cohort will receive NV1020 no earlier than 14 days after the last patient in the prior cohort has finished NV1020 infusions. One additional cohort (half log higher increment) may be approved by the DSMB, if considered necessary to define MTD. Dose-limiting toxicity will be determined using NCI CTC criteria and a suitable dose level for later evaluation will be selected.

In the second stage of the study, the dose cohort considered to show the best therapeutic index will be expanded by the addition of 18 further patients. For all patients in this study, investigational treatment with NV1020 will be followed by a minimum of two cycles of second-line therapy using anti-neoplastic drugs approved by the FDA for colorectal cancer and selected by the investigator.

All patients will be followed up periodically until death. Permission for autopsy will be sought.

Inclusion Criteria:

1. Ability to understand and willingness to sign a written informed consent (includes willingness to avoid physical intimacy during and for 2 weeks post NV1020 treatment)
2. 18 years or more of age
3. Colorectal adenocarcinoma histologically confirmed within one year prior to enrollment in the study
4. Liver dominant metastases (CT-measurable lesions with less than 50% total liver involvement), histologically confirmed
5. Failed conventional chemotherapy for metastatic disease (e.g. tumors no longer responding to 5-FU/leucovorin in combination with irinotecan or oxaliplatin with or without one monoclonal antibody)
6. Candidate for additional chemotherapy (and/or experimental anti-cancer therapy, if this is the only remaining treatment option)
7. Karnofsky Performance Status 70% or greater
8. Life expectancy greater than or equal to 4 months, based on the investigator's opinion
9. Seropositive for herpes simplex virus-1 (HSV-1)
10. Fecund females: negative for pregnancy test (urine or serum)
11. Effective double-barrier contraception for a minimum of 2 months following final infusion of NV1020

Exclusion Criteria:

1. Dominant extrahepatic disease, including cerebral metastases, significant malignant ascites or other extrahepatic metastases that are symptomatic, in critical locations or otherwise likely to confound NV1020 evaluations, in the opinion of the investigator

2. Seronegative for HSV-1

3. Significant active/unstable non-malignant disease or laboratory test (hematology and chemistry) results that meet any of the following:

   • White blood cell count (WBC) less than or equal to 3 x 10e3/mm3
   • Absolute neutrophil count (ANC) less than or equal to 1.5 x 10e3/mm3
   • Platelets less than or equal to 100,000/mm3
   • Hemoglobin (Hgb) less than or equal to 9.0 g/dL
   • Prothrombin time/partial thromboplastin time (PT/PTT) > upper limit of normal (ULN)
   • Serum creatinine > 2.0 mg/dL
   • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times ULN or total bilirubin > 1.5 times ULN
   • Alkaline phosphatase > 2.5 times ULN

4. Chemotherapy < 4 weeks prior to the first NV1020 infusion (mitomycin or nitrosurea < 6 weeks)

5. Immunotherapy < 6 weeks prior to the first NV1020 infusion

6. Radiotherapy (external or internal) to the liver

7. Major surgery (excluding pump placement and cholecystectomy) ≤ 2 weeks prior to the first NV1020 infusion but the subject must be clinically stable. Pump placement and cholecystectomy ≤ 1 week prior to the first NV1020 infusion but the subject must be clinically stable

8. Female who is pregnant or nursing

9. Patients wishing to conceive within 2 months after the last infusion of NV1020

10. Any investigational agent administered less than or equal to 4 weeks prior to NV1020 infusion

11. Acute HSV infection requiring systemic antiviral therapy or history of serious HSV infection (e.g., ocular, encephalitic, etc.)

12. Active viral hepatitis (evidence for infection with hepatitis A, B or C viruses)

13. Known infection with HIV

14. Known hypersensitivity to any component of the NV1020 formulation

15. History of, or current, bleeding or coagulation disorder

16. History of significant hepatic fibrosis, cirrhosis, or hemachromatosis

17. History of malignancy other than colorectal cancer, within 5 years prior to start of study participation, with the exception of in situ cervical or skin carcinoma

18. Active severe infection and any other concurrent disease or medical conditions that are likely to interfere with the study, as judged by the investigator

19. Systemic corticosteroid administration < 4 weeks prior to starting NV1020 treatment

20. Prior treatment with NV1020 or other putative oncolytic viruses