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.

Study Overview

• Status: Completed
• Conditions: Liver Neoplasms; Colorectal Cancer
• Intervention / Treatment: Drug: NV1020

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92093
      • University of California, San Diego
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • University of Vanderbilt
  • Texas
    • Dallas, Texas, United States, 75201
      • Mary Crowley Medical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Safety and antitumor effects of NV1020; Stage 1: Four escalating dose cohorts of NV1020 3x10^6 pfu, 1x10^7 pfu, 3x10^7 pfu, and 1x10^8 pfu administered via hepatic artery infusion, over 10 minutes and repeated every 1-2 weeks for 4-8 weeks followed by 2 cycles of chemotherapy. Stage 2: Expansion of one dose cohort from Stage 1 of optimal NV1020 dose administered via hepatic artery infusion, over 10 minutes and repeated every 1-2 weeks for 4-8 weeks followed by 2 cycles of chemotherapy.

Drug: NV1020; NV1020 dose levels: 3x10^6, 1x10^7, 3x10^7, and 1x10^8 plaque forming units, administered via hepatic artery infusion, over 10 minutes and repeated every 1-2 weeks for 4-8 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events and Dose Limiting Adverse Events	Incidence of adverse events for all patients (N=32); Overall incidence ≥20%; Adverse events listed by Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term	From start of treatment through 12 months after completion of treatment
NV1020 Pharmacokinetics - Presence of NV1020 in Body Fluids/Skin	Number of patients with NV1020 detected in saliva, skin, and/or mucosal surfaces; Analysis by polymerase chain reaction (PCR)	Daily for 2 weeks after the first and last NV1020 infusions
Clinical Laboratory Safety - Hematology	Number of patients with clinically significant hematology laboratory abnormalities by NV1020 dose cohort (Post baseline)	Screening; after each NV1020 infusion; +7h, +24h, and +72h after NV1020 infusion; each chemotherapy visit; +3d, +7d, +14d after each chemo visit; 1 week after end of treatment
Clinical Laboratory Safety - Chemistry	Number of patients with post-baseline clinically significant laboratory chemistry abnormalities by NV1020 dose cohort	Screening; after each NV1020 infusion; +7h, +24h, and +72h after NV1020 infusion; each chemotherapy visit; +3d, +7d, +14d after each chemo visit; 1 week after end of treatment
Clinical Laboratory Safety - Coagulation	Number of patients with post-baseline clinically significant laboratory coagulation abnormalities by NV1020 dose cohort	Screening; after each NV1020 infusion; +7h, +24h, and +72h after NV1020 infusion; each chemotherapy visit; +3d, +7d, +14d after each chemo visit; 1 week after end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Serum Carcinoembryonic Antigen (CEA) After Administration of NV1020 and 2 Cycles of Chemotherapy		Screening (baseline), Chemo visit 1, Chemo visit 2, Follow-up Visit 1 (1 week after end of treatment), Follow-up Visit 2 (+6M), Follow-up Visit 3 (+9M), Follow-up Visit 4 (+12M)
Liver Tumor Response After Administration of NV1020 Followed by Chemotherapy, Determined by Radiological (Computed Tomography [CT] Scan) Assessment	Maximum percentage changes in tumor diameter after administration of NV1020 followed by chemotherapy as measured by CT scan and Modified Response Evaluation Criteria in Solid Tumors (RECIST) assessment	Screening (baseline), Chemo visit 1, Follow-up visits 1 (1 week post end of treatment), 2 (+6M), 3 (+9M), 4 (+12M)
Pharmacodynamic Effects of NV1020: NV1020 Neutralizing Antibody Titer Assay	Mean change from baseline in NV1020 neutralizing antibody titer by dose cohort	Screening, Chemo Visit 1, Follow-up Visits 1 (1 week post end of treatment), 2 (+6M), 3 (+9M), 4 (+12M)
Time to Disease Progression; Survival Time	Progression assessed from CT and PET measurements and is determined as an increase of greater than or equal to 25% in the sum of the products of perpendicular diameters of all tumors, or the appearance of any new lesion.	Progression: Chemo visit 1, FU1 (1 week post treatment), FU2 (+6M), FU3 (+9M), FU4 (+12M); Survival: death of patient
Pharmacodynamic Effects of NV1020: Serum Cytokines (INF Gamma)	Median change from baseline of Interferon (INF) gamma 8 hours post NV1020 infusion (Visits 1, 3, 5, 7)	Baseline, after each NV1020 infusion (Visit 1, Visit 3, Visit 5, Visit 7)
Pharmacodynamic Effects of NV1020: Serum Cytokines (IL-6)	Median change from baseline of Interleukin-6 (IL-6) 8 hours post NV1020 infusion (Visits 1, 3, 5, 7)	Baseline, after each NV1020 infusion (Visit 1, Visit 3, Visit 5, Visit 7)
Pharmacodynamic Effects of NV1020: Serum Cytokines (TNF-alpha)	Median change from baseline of tumor necrosis factor (TNF-alpha) 8 hours post NV1020 infusion (Visits 1, 3, 5, 7)	Baseline, after each NV1020 infusion (Visit 1, Visit 3, Visit 5, Visit 7)

Collaborators and Investigators

• Sponsor: MediGene
• Investigators: Study Director: Hoda Tawfik, PhD, MediGene

Publications and helpful links

General Publications

• Sze DY, Iagaru AH, Gambhir SS, De Haan HA, Reid TR. Response to intra-arterial oncolytic virotherapy with the herpes virus NV1020 evaluated by [18F]fluorodeoxyglucose positron emission tomography and computed tomography. Hum Gene Ther. 2012 Jan;23(1):91-7. doi: 10.1089/hum.2011.141. Epub 2011 Oct 14.

Study record dates

Study Major Dates

• Study Start: July 1, 2004
• Primary Completion (Actual): October 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: September 6, 2005
• First Submitted That Met QC Criteria: September 6, 2005
• First Posted (Estimate): September 8, 2005

Study Record Updates

• Last Update Posted (Actual): April 24, 2018
• Last Update Submitted That Met QC Criteria: March 21, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Colorectal Cancer; Liver cancer; Colorectal Carcinoma; Colorectal Neoplasms; Liver Neoplasms; Colon cancer; Liver Tumors; Colorectal Tumors; Rectum Cancer; Colon Neoplasms; Hepatic Cancer; Hepatic Neoplasms; Hepatic tumors; Colon carcinoma; Rectum carcinoma; Colorectal cancer metastases to liver; Rectum tumors; Colon tumors; Rectum Neoplasms; metastatic to the liver
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Liver Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplasms; Colorectal Neoplasms; Liver Neoplasms
• Other Study ID Numbers: CT1030

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO