Vaccine Therapy and Radiation to Liver Metastasis in Patients With CEA-Positive Solid Tumors



Status:Completed
Conditions:Liver Cancer, Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:18 - Any
Updated:4/21/2016
Start Date:April 2004
End Date:August 2007

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A Pilot Trial of a CEA-TRICOM Based Vaccine and Radiation to Liver Metastasis in Adults With CEA Positive Solid Tumors

This study will evaluate the safety and effects of vaccine treatment plus radiation to the
liver in patients with solid tumors that have spread to the liver. The vaccine treatment
consists of three parts: 1) a "priming vaccine" called rV-CEA(6D)-TRICOM, made from vaccinia
virus; 2) a "boosting vaccine" called rF-CEA(6D)-TRICOM), made from fowlpox virus; and 3) a
fowlpox virus injected with DNA for GM-CSF, a chemical that boosts the immune system, called
rF-GM-CSF. Human DNA is inserted into the priming and boosting vaccine viruses to cause
production of proteins that enhance immune activity and also to produce carcinoembryonic
antigen (CEA) - a protein that is normally produced by the patient's tumor cells. The study
also uses radiation, because laboratory and animal studies show that low doses of radiation
to tumors that produce CEA make the tumor more sensitive to the effects of the vaccines.

Patients 18 years of age and older who have a solid tumor that has spread to the liver may
be eligible for this study. Candidates must have had at least one course of chemotherapy for
metastatic disease and their tumor must produce CEA. Candidates are screened with a medical
history and physical examination; blood and urine tests, test of pathology slides from
surgery to determine the presence of the CEA marker, imaging studies to assess the extent of
tumor, and an electrocardiogram (and cardiologic evaluation, if clinically indicated).

Participants receive the priming vaccination on study day 1. After 3 weeks and then again
every 2 weeks for 2 months (study days 21, 35, 49 and 63), they receive a boosting vaccine.
All vaccines are injected under the skin. With every vaccination they also receive an
injection of rF-GM-CSF to increase the number of immune cells at the vaccination site. The
day after each of the first four boosting vaccinations, patients undergo 4 consecutive days
of radiation to the tumor in the liver (study days 22-25, 36-39, 50-53 and 64-67). Patients
may continue treatment with monthly booster vaccinations (without further radiation therapy)
as long as their cancer does not get worse and they do not develop serious treatment side
effects.

Patients are monitored for safety and treatment response with the following tests and
procedures:

- Blood and urine tests and clinic visits every 2 to 4 weeks to monitor liver, kidney,
and other organ function.

- Imaging studies to assess the tumor around study day 91 and every 2 months after that
while on the study.

- Apheresis (a procedure for collecting immune cells called lymphocytes) - Apheresis is
done before the first vaccination on study day 1 and again around study day 91. For
this procedure, blood is collected through a needle in an arm vein. The blood
circulates through a machine that separates it into its components by spinning, and the
lymphocytes are extracted. The rest of the blood is returned to the patient through the
same needle. The collected lymphocytes are studied to measure the immune response to
treatment.

- Liver biopsy (optional) - This test is done once before starting radiation treatment
and again around 3 to 7 days after completing the first dose of radiation. The biopsy
provides information on the type of cancer, the level of CEA produced by the tumor, and
the immune status of the tumor. For this procedure, the skin over the liver is numbed
with an anesthetic, a needle is placed in the liver tumor, and a small sample of tumor
is withdrawn through the needle.

After treatment is completed, patients are monitored for up to 15 years, including yearly
medical histories and physical examinations for 5 years following their last vaccination.
Information beyond 5 years is collected once a year by telephone

Background:

- A phase I clinical trial with this same vaccine alone was associated with stable
disease (at least 4 months) in 40% of patients and 1 pathologic complete response.

- Radiation therapy upregulates Fas on tumor cells allowing for easier killing by antigen
specific activated T cells. Dominant negative fas transfected tumor cells demonstrated
the anti-tumor effects were fas mediated.

- Radiation has been shown to up-regulate ICAM, tumor associated antigens and MHC class I
on human tumor cell lines in vitro.

- TRICOM vaccines act synergistically with radiation in tumor treatment models.

- Radiation therapy at the doses we propose appears to have a favorable safety profile.

- Clinical trials using PSA vaccine shows that local radiation of tumor does not inhibit
vaccine efficacy.

Objectives:

- 1: Safety of the combination of a CEA based vaccine and radiation

- 2: clinical response

- 2: Immunohistochemistry - (FAS, MHC, p53 and CEA on tumor before and after radiation
therapy)

- 2: Immunological response (ELISPOT assay).

Eligibility:

- Solid Tumors expressing CEA positive cancer with radiographically visible metastatic
liver lesions.

- Completed at least one chemotherapy regimen for metastatic disease.

- Life expectancy greater than or equal to 6 months

- Adequate organ function

- ECOG 0-1

- No autoimmunity

- No serum positivity for HIV, Hepatitis B or C viruses

Design:

- Single cohort pilot study of vaccine and radiation therapy to liver lesions in 10
evaluable patients. All vaccines and radiation are given at the NIH Clinical Center.

- Vaccine:

rV-CEA(6D)/TRICOM, (1.2 x 10(8)) PFU subcutaneously (s.c.) day 1

rF-CEA(6D)/TRICOM, (4 x 10(8)) PFU s.c., days 21, 35, 49, and 63

All vaccinations will be given with rF-GM-CSF, 1 x 10(7) pfu s.c.

-Radiation: 2 Gy/d for 4 days after each dose of rF-CEA(6D)/TRICOM on days 22-25, 36-39,
50-53, and 64-67 (total planned radiation dose per patient is 32 Gy).

- INCLUSION CRITERIA

Solid Tumors expressing CEA positive cancer with radiographically visible metastatic liver
lesions. Tumor that has been shown to express CEA by positive immunohistochemical
techniques (staining of at least 20% of cells will be considered positive) or have had an
elevated serum CEA greater than 5 ng/ml at any point during their disease course.

Completed at least one chemotherapy regimen for metastatic disease.

18 years of age or greater.

Life expectancy greater than or equal to 6 months.

Able to understand and give informed consent.

ECOG performance status of 0 - 1.

Serum creatinine within the institution limits of normal OR creatinine clearance on a 24
hour urine collection of greater than or equal to 60 mL/min, AST less than or equal to
twice the institution upper limits of normal.

Total bilirubin less than the upper level of normal for that particular institution and if
patient has Gilbert's syndrome, is bilirubin less than or equal to 3.0.

Vaccinia-naive or vaccinia immune.

Recovered completely from any reversible toxicity associated with recent therapy.
Typically this is 3-4 weeks for patients who most recently received cytotoxic therapy
except for the nitrosoureas and mitomycin C for which 6 weeks is needed for recovery.

At least 4 weeks after cytotoxic therapy with complete recovery of reversible toxicity.

Hematological eligibility parameters (within 16 days of starting therapy):

Granulocyte count greater than or equal to1,500/mm(3).

Platelet count greater than or equal to 100,000/mm(3).

Hgb greater than or equal to 8 Gm/dL.

Absolute lymphocyte count greater than or equal to 400/mm(3).

PT/PTT within the institution limits of normal.

Prior Immunotherapy will be allowed

Serum Beta-HCG less than 5.0 microIU/mL in females (with child bearing potential).

EXCLUSION CRITERIA

Patients should have no evidence of being immunocompromised as listed below.

- Human immunodeficiency virus positivity due to the potential for decreased tolerance
and may be at risk for severe side effects

- Autoimmune diseases such as, Addison's disease, Hashimoto's thyroiditis, or systemic
lupus erythematous, Sjogren syndrome, scleroderma, myasthenia gravis, Goodpasture
syndrome active Grave's disease. Altered immune function in prospective participants
will be assessed through a thorough history and physical examination. Any clinical
suspicion of autoimmune dysfunction will be worked up before enrollment on to the
study. This requirement is due to the potential risks of exacerbating autoimmunity

- Hepatitis B or C positivity

- Prior radiation to greater than 50% of all nodal groups

- Prior whole liver radiation

- Concurrent use of systemic steroids, except for physiologic doses for systemic
steroid replacement or local (topical, nasal, or inhaled) steroid use. Steroid eye
drops are contraindicated for at least 2 weeks prior vaccinia vaccination and at
least 4 weeks post vaccinia vaccination.

- Prior splenectomy

History of allergy or untoward reaction to prior vaccination with vaccinia virus or to any
component of the vaccinia vaccine regimen.

Pregnant or breast-feeding women.

Recombinant vaccinia vaccination should not be administered if any of the following apply
to either recipients, or for at least three weeks after vaccination (i.e., until the scab
has separated from the skin and the underlying skin has healed), their close household
contacts (close household contacts are those who share housing or have close physical
contact): persons with active or a history of eczema or other eczematoid skin disorders;
those with other acute, chronic or exfoliative skin conditions (e.g., atopic dermatitis,
burns, impetigo, varicella zoster, severe acne, or other open rashes or wounds) until
condition resolves; pregnant or nursing women; children 5 years of age and under; and
immunodeficient or immunosuppressed persons (by disease or therapy), including HIV
infection.

Serious intercurrent medical illness which would interfere with the ability of the patient
to carry out the treatment program, including, but not limited to, inflammatory bowel
disease, Crohn's disease, ulcerative colitis, or active diverticulitis.

Known brain metastasis, history of seizures, encephalitis, or multiple sclerosis.

Concurrent chemotherapy.

Serious hypersensitivity reaction to egg products.

Clinically significant cardiomyopathy requiring treatment.

Patients with cardiac disease that have fatigue, palpitation, dyspnea or angina with
ordinary physical activity (New York Heart Association class 2 or greater) are not
eligible.

Patients with pulmonary disease that have fatigue or dyspnea with ordinary physical
activity are not eligible.

Patients who have objective evidence of congestive heart failure by physical exam or
imaging are not eligible.

Chronic liver disease including end stage cirrhosis, or chronic active hepatitis as
indicated by surface antigen or core antibody.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
?
mi
from
Bethesda, MD
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