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Tumor Site Specific Phase I Evaluation of Safety of Hepatic Arterial Infusion of a Matrix-Targeted Retroviral Vector Bearing a Dominant Negative Cyclin G1 Construct as Intervention for Colorectal Carcinoma Metastatic to Liver


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
Colorectal Neoplasms

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Trial Information

Tumor Site Specific Phase I Evaluation of Safety of Hepatic Arterial Infusion of a Matrix-Targeted Retroviral Vector Bearing a Dominant Negative Cyclin G1 Construct as Intervention for Colorectal Carcinoma Metastatic to Liver


Objectives:

1. To evaluate the safety/toxicity of hepatic arterial administration of a matrix-targeted
retroviral vector bearing a dnG1 construct (Mx-dnG1)

2. To evaluate the pharmacodynamics of hepatic arterial infusion of the Mx-dnG1 retroviral
vector administered as hepatic arterial infusion.

3. To obtain preliminary data on molecular markers of tumor response

4. To identify an anti-tumor response to hepatic artery administered Mx-dnG1 retroviral
vector

Population: Male and female patients, >18 years old, with metastatic colorectal carcinoma

Sample Size: Nine to fifteen patients (3 to 6 patients treated at each of three dose
levels).

Dosage Treatment: Hepatic arterial infusion of the Mx-dnG1 retroviral vector once a day on
days 1-5.

Three patients will receive the Mx-dnG1 retroviral vector at Dose Level I. If 1 of 3
patients at Dose Level I develops a grade 3 or 4 adverse event (CTC Version 2.0) which
appears to be related or possibly related to the Mx-dnG1 retroviral vector, then 3
additional patients will be enrolled at the same dose level. If at least 2 of the first 3,
or 3 of 6, patients at Dose Level I develop a grade 3 to 4 adverse event which appears to be
related or possibly related to the Mx-dnG1 retroviral vector, accrual into the study will be
held until the data are discussed with the Food and Drug Administration (FDA) and a decision
is made whether to continue or terminate study enrollment.

If none of the first 3 or no more than 1 of the first 6 patients that have received vector
at Dose Level I develop a grade 3 or 4 adverse event which appears to be related or possibly
related to the dnG1 retroviral vector, the dose of the vector will be escalated as follows:

Dose LeveL---No. of Patients---Vector Dose---Maximum Volume

- I----------------3------------3 X 10e9 cfu-------500 ml

- II---------------3------------6 X 10e9 cfu-------500 ml

- III--------------3------------1 X 10e10 cfu------500 ml

The intervention plan will be identical to the one described above for Dose Level I. The
Maximum Tolerated Dose (MTD) will be defined as one dose level below the level at which dose
limiting toxicity is observed.

Primary Endpoint: Clinical toxicity (DLT and MTD) as defined by patient performance
status, toxicity assessment score, hematologic, liver and coagulation profile.

Secondary Endpoint: Obtain preliminary data on molecular markers of tumor response. To
assess decrease in tumor size as detected by abdominal CT Scan at 3 and 6 weeks after
treatment. Evaluate the pharmacodynamics of hepatic arterial infusion of the Mx-dnG1
retroviral vector administered as hepatic arterial infusion.


Inclusion Criteria:

Patients will be considered candidates for the proposed protocol if
the patients have failed standard chemotherapy regimens (5-FU, LV and CPT-11), in the
judgment of the principal investigator, and meet the following criteria:

1. Histologically or cytologically confirmed colorectal carcinoma metastatic to liver,
which is unresectable based on the judgment of the patient's surgeon) and is
radiologically measurable.

2. Adequate hepatic function: Total bilirubin < 2.0 mg/dL (upper limit included);
AST/ALT < 2x institutional norm; alkaline phosphatase < 3x upper limit of
institutional norm, albumin > 3.0 mg/dL. There must be no substantial ascites. PT
and PTT must be within normal limits.

3. Performance status must be 0-1 (SWOG 0-1) with a life expectancy of at least 3
months.

4. Absolute granulocyte count > 1000/uL, and platelet count > 100,000/uL.

5. Calculated creatinine clearance > 60ml/hour.

6. There must be no plans for the patient to receive further cancer therapy from the
date of enrollment until the completion of the 12 week follow-up visit.

7. Installation of a functional hepatic arterial infusion (HAI) with satisfactory
positioning of the catheter in a primary branch of the hepatic artery, placed within
the prior 6 months to three weeks. If the patient does not presently have a hepatic
artery infusion pump in place, a pump can be placed for them so that they might
qualify to participate in the intervention and follow-up phases of this clinical
trial.

8. Age > 18 years, in order to protect children or minors from the potential risks of a
new drug that has not yet been tested in adults.

9. The ability to understand and the willingness to sign a written informed -consent
document.

Exclusion Criteria

1. Prior malignancy, except for non-melanoma skin cancer, stage I breast cancer, CIS of
cervix from which the patient has been disease free for 5 years.

2. Woman who are pregnant or nursing

3. Fertile patients unless they agree to use barrier contraception (condoms and
spermicide jelly) during the vector infusion period and for six weeks after infusion.

4. Patients with medical, psychiatric, or social conditions that would compromise
successful adherence to this protocol.

5. Patients with indwelling biliary stents or a recent history of cholangitis,
hepatitis, presence of disseminated intravascular coagulopathy, or HIV infection.
Patients must not have a history of recent myocardial infarction (within one year) or
evidence of congestive heart failure.

6. Patients with a history of bleeding varices in the prior 3 months.

7. Patients who have received any other antitumor treatment (chemotherapy, radiation,
immunotherapy) within 4 weeks of study entry or who have not recovered from previous
therapy or within 6 weeks for mitomycin C and nitrosureas.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

dose-limiting toxicity and maximum tolerated dose

Authority:

United States: Food and Drug Administration

Study ID:

3C-01-2

NCT ID:

NCT00035919

Start Date:

November 2002

Completion Date:

October 2003

Related Keywords:

  • Colorectal Neoplasms
  • Colon cancer
  • Targeted Injectable Vector
  • Gene Transfer
  • Gene Therapy
  • Retroviral vector
  • Neoplasms
  • Colorectal Neoplasms

Name

Location

USC Norris Comprehensive Cancer CenterLos Angeles, California  90089
USC General Clinical Research CenterLos Angeles, California  90089